Methods for treatment of lung damage and for inhibition of lung fibrosis

ABSTRACT

A method of stimulating the synthesis of human and animal patient lung and sinus surfactants for treatment of lung damage needed to increase lung functions, increase oxygen levels, increase the synthesis of nasal nitric oxide and for inhibition of lung fibrosis while reducing, coughing, lung tightness, mouth breathing, and reducing congestion, for treating patients with a pulmonary condition including asthma, chronic obstructive pulmonary disease, cystic fibrosis, interstitial lung disease, pulmonary fibrosis, allergic rhinitis, sinusitis, sleep apnea and lung cancer, includes: contacting mammalian cells with a therapeutically effective amount of a composition, said composition including the following constituents: 
     sodium pyruvate; a phosphate; a salt of calcium; and, a salt of magnesium. Preferably, the composition is a saline solution.

REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of United Statesco-pending utility application Ser. No. 15/441,552, filed on Feb. 24,2017, Official Docket No. CSI-011, and titled “Compositions and Methodsfor the Treatment and Prevention of Chronic Hypoxemia and Dyspnea” bythe same inventor herein.

BACKGROUND OF INVENTION a. Field of Invention

The present invention generally relates to methods utilizingcompositions that enhance the synthesis of lung surfactants that havebeen decreased by lung diseases or injuries. The present invention isbased on the discovery that the pulmonary dysfunction, characteristic ofcertain disease states, is attributable to the decrease in the synthesisof a number of surfactant and other secretory molecules normallyproduced by type II alveolar cells, leading to lung tightness, reducedlung capacity and function and volume, coughing, dyspnea and hypoxemia.

b. Description of Related Art

The following patents are representative of the field pertaining to thepresent invention:

U.S. Pat. No. 5,210,098 issued to Nath discloses a method to arrest orprevent acute kidney failure by administration of a non-toxic pyruvatesalt to a patient in need of such treatment. The Nath invention providesa therapeutic method comprising administration of an amount of pyruvatesalt to a patient experiencing, or in danger of, acute renal failure.

U.S. Pat. Nos. 3,920,835, 3,984,556, 3,988,470, and 4,234,599 all issuedto Van Scott et al. disclose methods for treating acne, dandruff, andpalmar keratosis, respectively, which consist of applying to theaffected area a topical composition comprising from about 1% to about20% of a lower aliphatic compound containing from two to six carbonatoms selected from the group consisting of alpha-hydroxy acids,alpha-ketoacids and esters thereof, and 3-hydroxybutryic acid in apharmaceutically acceptable carrier. The aliphatic compounds includepyruvic acid and lactic acid.

U.S. Pat. Nos. 4,158,057, 4,351,835, 4,415,576, and 4,645,764, allissued to Stanko, disclose methods for preventing the accumulation offat in the liver of a mammal due to the ingestion of alcohol, forcontrolling weight in a mammal, for inhibiting body fat while increasingprotein concentration in a mammal, and for controlling the deposition ofbody fat in a living being, respectively.

U.S. Pat. Nos. 5,798,388, 5,939,459, 5,952,384 and 6,623,723 to Katz andMartin, the inventor herein, pertain to methods for treatinginflammation in the lungs and compositions useful in the method. Themethod comprises contacting the mammalian cells participating in theinflammatory response with an inflammatory mediator. The inflammatorymediator is present in an amount capable of reducing the undesiredinflammatory response and is an antioxidant.

U.S. Pat. No. 6,689,810 to Martin, the inventor herein, discloses atherapeutic composition for treating pulmonary diseases states inmammals by altering indigenous in vivo levels of nitric oxide. Thetherapeutic composition consists of pyruvates, pyruvate precursors,alpha-keto acids having four or more carbon atoms, precursors ofalpha-keto acids having four or more carbons, and the salts thereof.Martin also claimed that all salts of pyruvate were equal.

U.S. Pat. Nos. 8,076,373 and 8,114,907 Martin, the inventor herein,discloses a method for treating pulmonary disease state in mammals by upor down regulating in vivo levels of inflammatory agents (cytokines) inmammalian cells.

United States Patent Application Publication No. 2009/0181007 to Genneroet al describes a composition for in vitro use to create a culturemedium for accelerating the differentiation of stem cells into cellswith a chondrocytes phenotype and for restoring the original trophism ofchondrocytes, to increase the synthesis of collagen, to repair jointdamage. The increase in collagen deposition increases fibrosis. Thisprior art reference, as well as some Katz et al references, were citedin the parent application of this instant application and are discussedin more detail below.

SUMMARY OF THE INVENTION

The present invention is directed to a method of stimulating thesynthesis of human and animal patient lung and sinus surfactants fortreatment of lung damage needed to increase lung functions, increaseoxygen levels, increase the synthesis of nasal nitric oxide and forinhibition of lung fibrosis while reducing, coughing, lung tightness,mouth breathing, and reducing congestion, for treating patients with apulmonary condition including asthma, chronic obstructive pulmonarydisease, cystic fibrosis, interstitial lung disease, allergic rhinitis,chronic rhinosinusitis, sleep apnea and lung cancer. This methodincludes contacting mammalian cells with a therapeutically effectiveamount of a composition, said composition including the followingconstituents: sodium pyruvate; a phosphate; a salt of calcium; and, asalt of magnesium wherein said composition contains the followingamounts of said constituents: sodium pyruvate ranges from about 0.0001mg to about 1 gram; and ranges from 0.0001 mg to about 1 gram for eachof the following constituents: phosphate, salt of calcium and salt ofmagnesium.

In some preferred embodiments of the present invention method, thecomposition is a saline solution. In some preferred embodiments of thepresent invention method, the phosphate is selected from the groupconsisting of calcium phosphate, a potassium phosphate, magnesiumphosphate, and zinc phosphate, and combinations thereof. In somepreferred embodiments of the present invention method, the phosphate isa calcium phosphate selected from the group consisting of calciumphosphate, di-calcium phosphate and combinations thereof. In somepreferred embodiments of the present invention method, the phosphate isa potassium phosphate selected from the group consisting of potassiumphosphate, di-potassium phosphate, tri-potassium phosphate, andcombinations thereof. In some preferred embodiments of the presentinvention method, the salt of calcium is selected from the groupconsisting of calcium chloride, calcium carbonate, calcium acetate,calcium citrate, calcium lactate, calcium sulfate, and combinationsthereof. In some preferred embodiments of the present invention method,the salt of magnesium is selected from the group consisting of magnesiumchloride, magnesium phosphate, magnesium sulfate, magnesium bicarbonate,and combinations thereof.

In some preferred embodiments of the present invention method, thephosphate is selected from the group consisting of calcium phosphate, apotassium phosphate, magnesium phosphate, and zinc phosphate, andcombinations thereof, and wherein said salt of magnesium is selectedfrom the group consisting of magnesium chloride, magnesium phosphate,magnesium sulfate, magnesium bicarbonate, and combinations thereof. Insome preferred embodiments of the present invention method, the salt ofmagnesium is selected from the group consisting of magnesium chloride,magnesium phosphate, magnesium sulfate, magnesium bicarbonate, andcombinations thereof, and wherein said salt of calcium is selected fromthe group consisting of calcium chloride, calcium carbonate, calciumacetate, calcium citrate, calcium lactate, calcium sulfate, andcombinations thereof. In some preferred embodiments of the presentinvention method, the phosphate is selected from the group consisting ofcalcium phosphate, a potassium phosphate, magnesium phosphate, and zincphosphate, and combinations thereof, and wherein said salt of calcium isselected from the group consisting of calcium chloride, calciumcarbonate, calcium acetate, calcium citrate, calcium lactate, calciumsulfate, and combinations thereof.

In some preferred embodiments of the present invention method, thephosphate is selected from the group consisting of calcium phosphate, apotassium phosphate, magnesium phosphate, and zinc phosphate, andcombinations thereof, and wherein said salt of magnesium is selectedfrom the group consisting of magnesium chloride, magnesium phosphate,magnesium sulfate, magnesium bicarbonate, and combinations thereof, andwherein said salt of calcium is selected from the group consisting ofcalcium chloride, calcium carbonate, calcium acetate, calcium citrate,calcium lactate, calcium sulfate, and combinations thereof.

In some most preferred embodiments of the present invention method, thecomposition is a saline solution containing sodium pyruvate, calciumchloride, potassium phosphate and magnesium chloride ions in solution.

In some preferred embodiments of the present invention method, thecomposition contains the following amounts of said constituents: sodiumpyruvate ranges from about 0.01 mg to about 1 gram; and ranges from0.0001 mg to about 1 gram for each of the following constituents:phosphate, salt of calcium and salt of magnesium. In some more preferredembodiments of the present invention method, the composition containsthe following amounts of said constituents: sodium pyruvate ranges fromabout 0.01 mg to about 1 gram; and ranges from 0.0001 mg to about 1 gramfor each of the following constituents: phosphate, salt of calcium andsalt of magnesium.

In some preferred embodiments of the present invention method, atherapeutic agent is administered prior to contacting said mammaliancells with said composition. In some preferred embodiments of thepresent invention method, a therapeutic agent is administeredsimultaneously with contacting said mammalian cells with saidcomposition. In some preferred embodiments of the present inventionmethod, a therapeutic agent is administered after contacting saidmammalian cells with said composition.

In some preferred embodiments of the present invention method, themethod includes cancer treatment and an oral diet is administered beforeand after said cancer treatment and said oral diet includes any of thecompositions set forth above.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the discovery that the pulmonarydysfunction, characteristic of certain disease states is attributable tothe decrease in the synthesis of surfactants and other secretorymolecules normally produced by type II alveolar cells. This decrease insynthesis is believed to be caused by the low levels of key lungnutrients that results in abnormally functioning mitochondria in alveolileading to lung tightness, reduced lung capacity and functions andvolume, coughing, dyspnea and Hypoxemia. It is believed that nutrientdepleted or injured or damaged alveoli's cause a generalized decrease inthe normal rate of membrane trafficking within the type II cells resultsin a generalized defect in the synthesis and secretory process,including secondary effects which involve a significant decrease in thelevel of the synthesis of membrane phospholipids. Type II (GreatAlveolar) cells that secrete pulmonary surfactants needed to lower thesurface tension of water and allows the membrane to separate, thereforeincreasing its capability to exchange gases that maintain SaO2 oxygensaturation at or near 100%. Surfactant is continuously released byexocytosis. It forms an underlying aqueous protein-containing hypo phaseand an overlying phospholipid film composed primarily of dipalmitoylphosphatidylcholine.

This decrease in the synthesis of surfactants in turn causes an increasein surface tension of the aqueous film bathing the luminal aspect of thealveolar space, a decrease in the elastic properties of pulmonarytissue, a concomitant decrease in the rate of gas exchange within thealveolus, and an overall decrease in pulmonary function causing lungtightness, breathlessness, increased coughing, and a decrease in lungcapacity. As a result, the patient develops a pulmonary diseasesyndrome, including hampered breathing and inefficient gas exchange,with low SaO₂ levels called chronic hypoxemia. Reinflation of thealveoli following exhalation is made easier by pulmonary surfactant,which is a phospholipid and protein mixture that reduces surface tensionin the thin fluid coating within all alveoli. Insufficient pulmonarysurfactant in the alveoli can contribute to atelectasis (collapse ofpart or all of the lung). Without pulmonary surfactant, atelectasis is acertainty; however, there are other causes of lung collapse such astrauma (pneumothorax), COPD, and pleuritis.

Decrease in lung surfactants also cause coughing and breathlessness.Cough is usually the first symptom to develop. It is productive withsputum (phlegm). It tends to come and go at first, and then graduallybecomes more persistent (chronic). You may think of your cough as a‘smokers cough’ in the early stages of the disease. It is when thebreathlessness begins that people often become concerned.

Breathlessness (‘shortness of breath’) and wheezing may occur only whenyou exert yourself at first, for example, when you climb stairs. Thesesymptoms tend to become gradually worse over the years if you continueto smoke. Difficulty with breathing may eventually become quitedistressing. The damaged airways generally make a lot more mucus thannormal. This forms sputum (phlegm). You tend to cough up a lot of sputumeach day. Chest infections are more common if you have COPD. Wheezingwith cough and breathlessness may become worse than usual if you have achest infection. Sputum usually turns yellow or green during a chestinfection.

The phosphatidylcholine in some organs contains relatively highproportions of desaturated molecular species. For example, it is wellknown that lung phosphatidylcholine in most if not all animal speciesstudied to date contains a high proportion (50% or more) of dipalmitoylphosphatidylcholine. It appears that this is the main surface-activecomponent, providing alveolar stability by decreasing the surfacetension at the alveolar surface to a very low level. Also, the internallipids of the animal cell nucleus (after the external membrane has beenremoved) contain a high proportion of desaturated phosphatidylcholine,amounting to 10% of the volume indeed. This is synthesized entirelywithin the nucleus, unlike phosphatidylinositol for example, and incontrast to other cellular lipids its composition cannot be changed byextreme dietary manipulation. The components of pulmonary surfactant aresynthesized in the Golgi apparatus of the endoplasmic reticulum of thetype II alveolar cell and the secretion is induced by endoplasmicreticulum Ca₂ ATP-ase. Infant respiratory distress syndrome (IRDS) is asyndrome caused by lack of surfactant in the lungs of premature infants.

Hypoxemia is to be understood as and refers to low oxygen in the bloodwhich reduces oxygen to the whole body. Hypoxia is abnormally low oxygencontent in any tissue or organ caused by injury, disease or drugs.Patients can have hypoxia, without suffering from Hypoxemia. The two areseparate diseases. Chronic hypoxemia symptoms also include lungtightness, breathlessness, coughing, low lung capacity and volume.Hypoxemia can be caused by injury to the lungs, caused by lung and sinusdiseases and infections, including COPD, chemicals, ozone, lung cancer,and a host of medications that can injure lung cells and decrease theproduction of lung surfactants. Patients with hypoxemia are usually onoxygen therapy. Hypoxemia is usually defined in terms of reduced partialpressure of oxygen (mm Hg) in arterial blood, but also in terms ofreduced content of oxygen (ml oxygen per dl blood) or percentagesaturation of hemoglobin (the oxygen binding protein within red bloodcells) with oxygen, which is either found singly or in combination. Inan acute context, hypoxemia can cause symptoms such as those inrespiratory distress. These include breathlessness, an increased rate ofbreathing, use of the chest and abdominal muscles to breathe, and lippursing. However, in a chronic context, and if the lungs are not wellventilated generally, this mechanism can result in pulmonaryhypertension, overloading the right ventricle of the heart and causingcor pulmonale and right sided heart failure. Polycythemia can alsooccur. In children, chronic hypoxemia may manifest as delayed growth,neurological development and motor development and decreased sleepquality with frequent sleep arousals. Other symptoms of hypoxemia mayinclude cyanosis, and digital clubbing. Severe hypoxemia can lead torespiratory failure. Many patients with lung or sinus diseasesexperience Hypoxemia. It can be due to the destruction of the alveoli inthe lungs or the inadequate production of lung surfactants that enhanceoxygen up take. Hypoxemia can occur in patients with and without lung orsinus diseases, in patients with lung infections, heavy metal poisoningwith metals like cyanide, and the use of inhaled or non-inhaled drugs.It must be noted that there is a difference between people who havetransient hypoxemia vs. one that has permanent hypoxemia. The patientsrespond differently to the inhalation of sodium pyruvate by itselfwithout calcium, phosphate and magnesium. Sodium pyruvate in salinegiven both orally or by inhalation will increase _(SaO2) levels inpeople without hypoxemia. Transient hypoxemia (hypoxic endurance) is aself-correcting effect and does not involve lung injury or the inabilityto synthesize lung surfactants. It occurs in over exercising, mountainclimbing etc.

In controlled inhalation studies, patients without hypoxemia, lunginjuries or diseases, that produce normal levels of lung surfactants,have shown an increase of _(SaO2) by an average of 2%-3% when treatedwith sodium pyruvate in saline especially after exercising. Sodiumpyruvate solution was administered in sterile water via a nebulizer to54 patients and 15 healthy subjects, and the concentrations of nitricoxide exhaled from patients/healthy subjects were measured, as weretheir oxygen saturation levels. Pyruvate was administered in a nebulizer5 ml at one time.

The pyruvate concentrations were 0.5 mMol, 1.5 mMol, 5.0 mMol and 20mMol. Each concentration was inhaled once per day. Prior to theinhalation of pyruvate, nitric oxide measurements were taken, as wereoxygen saturation levels. Those levels were then taken one hour afterthe inhalation of the pyruvate solutions. The results showed that the 5mM and 20 mM solution increased nitric oxide levels by 22% in allsubjects. Saline alone did not increase nitric oxide levels or _(SaO2)in any subject. Oxygen saturation was increased by 3% in these patients.

In controlled inhalation studies, performed as part of this patent,patients with hypoxemia or lung injuries or diseases, and a decreasedability to synthesize lung surfactants, did not show an increase of_(SaO2) or nitric oxide when treated with inhaled sodium pyruvate insaline alone, and did not show a reduction in lung tightness, Dyspnea,coughing and increase lung capacity or volume.

Hypoxia in Cancer Cells:

Small cell lung cancer (SCLC) is an extremely aggressive disease forwhich minimal therapeutic improvements have been made over the last fewdecades. Patients still rely on non-targeted, chemotherapeutic drugscomplemented by irradiation. Although initial response is very good, themajority of SCLC patients invariably relapse with therapy-resistanttumors. Despite the link between pathologically low oxygen levels andtherapy resistant tumors, hypoxia has gained little attention in thedevelopment of novel therapies for SCLC. In contrast, the advantages oftargeting hypoxic cells in many other cancer types have been studiedextensively. Hypoxia is an important factor in tumor biology and is botha predictive and a prognostic factor in non-small cell lung cancer. Thenegative effect of low oxygenation on radiation therapy effect has beenknown for decades, but more recent research has emphasized that hypoxiaalso has a profound effect on a tumor's aggression and metastaticpropensity. Hypoxia is prevalent in small cell lung cancer (SCLC) tumorsand leads to cellular adaptations associated with aggressive tumors.Many methods of targeting hypoxia for cancer therapy have been explored;however, this treatment remains relatively under-investigated for SCLC.

Low oxygen levels in cells may be a primary cause of uncontrollabletumor growth in some cancers, according to a new University of Georgiastudy. The authors' findings run counter to widely accepted beliefs thatgenetic mutations are responsible for cancer growth. If hypoxia, or lowoxygen levels in cells, is proven to be a key driver of certain types ofcancer, treatment plans for curing the malignant growth could change insignificant ways.

The research team analyzed samples of messenger RNA data—also calledtranscriptomic data—from seven different cancer types in a publiclyavailable database. They found that long-term lack of oxygen in cellsmay be a key driver of cancer growth. The study was published in theearly online edition of the Journal of Molecular Cell Biology.

Previous studies have linked low oxygen levels in cells as acontributing factor in cancer development, but not as the driving forcefor cancer growth. High incidence rates of cancer around the worldcannot be explained by chance genetic mutations alone.

In their study, the researchers analyzed data downloaded from theStanford Microarray Database via a software program to detect abnormalgene expression patterns in seven cancers: breast, kidney, liver, lung,ovary, pancreatic and stomach.

They relied on the gene HIF1A as a biomarker of the amount of molecularoxygen in a cell. All seven cancers showed increasing amounts of HIF1A,indicating decreasing oxygen levels in the cancer cells.

Low oxygen levels in a cell interrupt the activity of oxidativephosphorylation, a term for the highly efficient way that cells normallyuse to convert food to energy. As oxygen decreases, the cells switch toglycolysis to produce their energy units, called ATP. Glycolysis is adrastically less efficient way to obtain energy, and so the cancer cellsmust work even harder to obtain even more food, specifically glucose, tosurvive. When oxygen levels dip dangerously low, angiogenesis, or theprocess of creating new blood vessels, begins. The new blood vesselsprovide fresh oxygen, thus improving oxygen levels in the cell and tumorand slowing the cancer growth but only temporarily.

This patent highlights various treatment options available forincreasing lung surfactants that are responsible for increasing bloodoxygen levels in cancer Patients thus targeting hypoxic cells withintumors that could be highly beneficial in the treatment of SCLC.

List of Conditions and Drugs that Impair the Synthesis of LungSurfactants that Cause Chronic Hypoxemia:

Hypoxemia is caused by insufficient synthesis of lung surfactants thatdecreases lung gas exchange, increases lung tightness, coughing anddecreases lung capacity. Hypoxemia can be caused by malnutrition, byinjury to the lungs, caused by lung and sinus diseases like COPD andasthma, and infections, chemicals, ozone, lung cancer, pulmonary edema,bronchiectasis, bronchiolitis, emphysema, bronchial pneumonia, allergicbronchopneumonia, Allergic Rhinitis, viral pneumonia, Respiratory mucus,nasal congestion, and encephalitis with retained secretions and a hostof medications that can injure lung cells that synthesize lungsurfactants. Patients with hypoxemia are usually on oxygen therapy.

Medications Administered by Respiratory Therapy that Cause Hypoxemia:

The inhaled drugs listed below have some or many of these adverseeffects: Hypoxemia, Chest pain, nausea, vomiting, coughing,bronchospasm, headaches, hypoventilation, hypotension, bradycardia,increased infections, blurred vision, mucosal irritation, fatigue, andshortness of breath. Epinephrine, Racemic Epinephrine (Vaponephrine),Beta-Sympathomimetics:Isoetharine (Bronkosol), Beta 2 agonist:Metaproterenol (Alupent), Albuterol (Proventil, Ventolin), Terbutaline,(Brethine, Bricanyl) Salmeterol (Serevent), Lev-albuterol (Xopenex),Nonsteroidal Anti-Inflammatory Agents: Cromolyn Sodium (Intal),Nedocromil sodium Tilade, Corticosteroids aerosolized Steroids: a.Dexamethasone (Decadron) b. Beclomethasone (Vanceril, beclovent) c.Triamcinolone (Azmacort) d. Flunisolide (Aerobid) e. Fluticasonepropionate (Flovent-a glucocorticoid) f. Budesonide Suspension(Pulmocort), Anticholinergics: Atropine, Ipratropium Bromide (Atrovent).

Mucolytics/Surface Active Agents Acetylcysteine (Mucomyst).AntiProtozoal Agent:

Pentamidine Isethionate (Nebupent) Combination drugs: Combivent(Ipratropium bromide and albuterol sulfate): Advair Diskus (salmeteroland Flovent), Recombinant Human Deoxy ribonuclease I Solution: DornaseAlfa (Pulmozyme, 25 Anti-Viral Agent: Virazole (Ribavirin), Antibiotic:Tobramycin (Tobi) Aminoglycoside antibiotic to treat Pseudomonasaeruginosa, Cancer drugs that increase hypoxemia include3-Bromopyruvate, 2-Deoxy-D-glucose, Dichloroacetic acid, andAcetylcysteine. Antioxidants have been shown to inhibit damageassociated with active oxygen species. For example, pyruvate and otheralpha ketoacids have been reported to react rapidly andstoichiometrically with hydrogen peroxide to protect cells fromcytolytic effects, O'Donnell-Tormey et al., J. Exp. Med., 165, pp.500-514 (1987). U.S. Pat. No. 5,210,098, cited above, issued to Nathdiscloses a method to arrest or prevent acute kidney failure byadministration of a non-toxic pyruvate salt to a patient in need of suchtreatment. The Nath invention provides a therapeutic method comprisingadministration of an amount of pyruvate salt to a patient experiencing,or in danger of, acute renal failure. As mentioned, U.S. Pat. Nos.3,920,835, 3,984,556, 3,988,470, and 4,234,599 all issued to Van Scottet al. disclose methods for treating acne, dandruff, and palmarkeratosis, respectively, which consist of applying to the affected areaa topical composition comprising from about 1% to about 20% of a loweraliphatic compound containing from two to six carbon atoms selected fromthe group consisting of alpha-15 hydroxy acids, alpha-ketoacids andesters thereof, and 3-hydroxybutryic acid in a pharmaceuticallyacceptable carrier. The aliphatic compounds include pyruvic acid andlactic acid.

Pyruvate has been reported to exert a positive inotropic effect instunned myocardium, which is a prolonged ventricular dysfunctionfollowing brief periods of coronary artery occlusions which does notproduce irreversible damage, Mentzer et al., Ann. Surg., 209, pp0.629-633 (1989).

U.S. Pat. Nos. 4,158,057, 4,351,835, 4,415,576, and 4,645,764, allissued to Stanko, disclose methods for preventing the accumulation offat in the liver of a mammal due to the ingestion of alcohol, forcontrolling weight in a mammal, for inhibiting body fat while increasingprotein concentration in a mammal, and for controlling the deposition ofbody fat in a living being, respectively.

U.S. Pat. Nos. 5,798,388, 5,939,459, 5,952,384 and 6,623,723 (Katz)pertain to methods for treating inflammation in the lungs andcompositions useful in the method. The method comprises contacting themammalian cells participating in the inflammatory response with aninflammatory mediator. The inflammatory mediator is present in an amountcapable of reducing the undesired inflammatory response and is anantioxidant.

U.S. Pat. No. 6,689,810 (Martin) discloses a therapeutic composition fortreating pulmonary diseases states in mammals by altering indigenous invivo levels of nitric oxide. The therapeutic composition consists ofpyruvates, pyruvate precursors, □-keto acids having four or more carbonatoms, precursors of □-keto acids having four or more carbons, and thesalts thereof. Martin also claimed that all salts of pyruvate wereequal.

U.S. Pat. Nos. 8,076,373 and 8,114,907 (Martin) discloses a method fortreating pulmonary disease state in mammals by up or down regulating invivo levels of inflammatory agents (cytokines) in mammalian cells.

While the above therapeutic compositions and methods are reported toinhibit the production and reduce the amount of reactive oxygenintermediates, such as hydrogen peroxide, peroxynitrite or nitric oxideand reduce inflammation, none of the disclosures describe a method andunique formula composition for enhancing the synthesis of lungsurfactants, to increase oxygen saturation values (_(SaO2)), increasenitric oxide generation, decrease coughing, reduce drug side effectswhich cause hypoxemia, reduce lung tightness, reduce the frequency oflung infections, and enhance drug uptake and efficacy in patients withhypoxemia, with and without lung or sinus diseases. Hypoxemia can becaused by injury to the lungs, caused by lung and sinus diseases andinfections, including COPD, chemicals, ozone, lung cancer, and a host ofmedications that can impair the synthesis of lung surfactants. A numberof these patents have claimed that all salts of pyruvate were equal. Wehave shown in this patent that not all salts of pyruvate are equal andwhen tested in humans, the zinc, manganese, aluminum, ammonium, andlithium did not increase FEV-1 or _(SaO2) levels or reverse Hypoxemia ordecrease oxygen radicals as well as sodium pyruvate did. They were infact irritating.

While the method for treating insufficient lung surfactants that causehypoxemia in mammalian nasal and sinus cells involved in the diseaseherein described constitute preferred embodiments of this invention, itis to be understood that the invention is not limited to this preciseform or method and that changes may be made therein without departingfrom the scope of the invention which is defined in the appended claims.Thus, the sodium pyruvate solution with concentrations of calcium,phosphate and magnesium as claimed according to the present inventionwas superior and was synergistic over our standard sodium pyruvateformula in saline in enhancing the production of surfactants needed toimprove lung functions in patients with Hypoxemia and to increase SaO2values, increase nitric oxide, reduce coughing, reduce lung tightnessand reduce lung infections. We have shown that a sodium pyruvate withcalcium, phosphate and magnesium formula can reduce the concentrationsof inhaled steroids and produce equal or better results.

The present invention utilizes pyruvate delivered in an inhaled sodiumpyruvate formula with calcium, phosphate and magnesium (a surfactantenhancer) that will enhance the synthesis lung and sinus surfactants,phospholipids in lung cells to enhance gas exchanges in the lung,increases oxygen saturation levels (SaO2) that facilitates the removalof excess mucus that can block the efficacy of inhaled drugs, therebyenhancing drug uptake and efficacy, while reducing, congestion,breathlessness, coughing, lung tightness, and increasing lung functions.Lung surfactants are mostly phospholipids which are synthesized in thelungs and sinuses.

Without these critical phospholipids, in mitochondria, the lung cellwould die. Most inhaled drugs cause damage to alveoli and decrease thesynthesis of lung surfactants needed to maintain normal lung functions.This therapy consists of contacting the lung or nasal cells with atherapeutically effective amount of the lung surfactant enhancer, aloneor in combination with inhaled drugs. Wherein the drugs are selectedform antivirals, antihistamines, antibacterials, antifungal, proteins,steroids, cytokines, nonsteroidal anti-inflammatory agents,antioxidants, insulin, nicotine and anticancer drugs wherein the lungsurfactant enhancer is selected from the group consisting of pyruvatesand pyruvate precursors, various salts of calcium, phosphates andmagnesium which enhance the synthesis of lung surfactants to decreasehypoxemia. Previous patents have claimed that pyruvate will work withantibacterials, antivirals, antifungals, antihistamines, proteins,enzymes, hormones, nonsteroidal anti-inflammatories, cytokines, andsteroids. We have found that sodium pyruvate will work with some drugsand not with others and that an inhaled formula of sodium pyruvate,calcium, phosphate and magnesium was superior to sodium pyruvate byitself. This new formula increases _(SaO2) values, reduced coughing andlung tightness and increased lung capacity in patients with chronichypoxemia including patients with COPD and asthma and in patientswithout any lung or sinus diseases. The surfactant enhancer of thepresent invention may be administered prior to, after and/or with othertherapeutic agents. Obviously, numerous modifications and variations ofthe present invention are possible in the light of the above teachingsand the invention is not limited to the example herein. It is thereforeunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described herein.

The present invention provides novel methods for treating insufficientsynthesis of surfactants in patients with non-pulmonary and pulmonarydiseases or nasal diseases state in mammals with a formula comprising atherapeutically effective amount of a surfactant enhancer which isselected from the group consisting of pyruvates and pyruvate precursorssolution containing the correct concentrations of calcium, phosphate andmagnesium. Pyruvate provides both the energy in the form of ATP toenhance the synthesis of lung surfactants and as a component of thephospholipids in lung surfactants, calcium and magnesium provide thesalts needed by cellular enzymes that produce cellular phospholipids andphosphate is essential component of all phospholipids that makeup alllung and sinus surfactants. Magnesium is also needed for mitochondrialmembrane stability and for the production of ATP. This is a uniquesynergistic formula.

The present invention has shown that no inhaled formulas with sodiumpyruvate in saline, to date, have been shown to enhance the synthesis oflung and sinus surfactants or increase _(SaO2) values for the treatmentof chronic hypoxemia and that only the combination of sodium pyruvatewith calcium, phosphate, and magnesium was synergistic in its abilityenhance the synthesis of lung surfactants, that enhance lung oxygensaturation (_(SaO2)) and FEV1 values, and reduce lung tightness,breathlessness, coughing, reduce the number of lung or sinus infection,reduce drug side effects that cause hypoxemia. Low _(Sa02) in humans iscalled Hypoxemia and can occur in patients with and without lung andsinus diseases, cancer and other conditions that injure lung tissuesthat will increase mucus production, fatigue, shortness of breath andincreased susceptibility to all types of infections. Lung and sinussurfactants mostly phospholipids, cannot be inhaled because they willblock oxygen uptake. The salt of calcium can be delivered as calciumphosphate, dicalcium phosphate, and as calcium pyruvate, calciumchloride or calcium citrate or many other forms. The phosphate can bedelivered as calcium phosphate, potassium phosphate, magnesium phosphateand in other ways. Magnesium can be delivered as magnesium chloride,magnesium phosphate, or magnesium bicarbonate and magnesium sulfate. Thesodium pyruvate formula with calcium, phosphate and magnesium actedsynergistically to enhance the synthesis of key cellular phospholipids,thus enhance the synthesis of lung surfactants that enhance lung alveolifunctions and oxygen saturation _(SaO2) values, better than the use ofsodium pyruvate or calcium pyruvate formulations by themselves or incombination.

Lung surfactants are mostly phospholipids which are synthesized in thecell and mitochondria. Without these critical phospholipids, especiallycardiolipin found in mitochondria, the lung cell would die. Thisthree-component system includes pyruvate, which become a component ofsynthesized lung surfactants, and calcium and magnesium provides thesalts needed by cellular enzymes that produce cellular phospholipids,magnesium is needed for mitochondrial membrane stability and theproduction of ATP, and phosphate is essential component of allphospholipids the makeup all lung and sinus surfactants. Magnesium is anessential element in biological systems. Magnesium occurs typically asthe Mg²⁺ ion. It is an essential mineral nutrient (i.e., element) forlife and is present in every cell type in every organism. For example,ATP (adenosine triphosphate), the main source of energy in cells, mustbe bound to a magnesium ion in order to be biologically active. What iscalled ATP is often actually Mg-ATP. As such, magnesium plays a role inthe stability of all polyphosphate compounds in the cells, includingthose associated with the synthesis of DNA and RNA. Over 300 enzymesrequire the presence of magnesium ions for their catalytic action,including all enzymes utilizing or synthesizing ATP, or those that useother nucleotides to synthesize DNA and RNA. Patients with chronicHypoxemia have low magnesium levels in the lungs that impair lung enzymefunctions.

The inhalation of sodium pyruvate with calcium, phosphate and magnesium(surfactant enhancer) also enhanced drug uptake and efficacy, reducinghypoxemia caused by inhaled drugs. The surfactant enhancer formula wassuperior over the sodium pyruvate saline formulations used in the pastwithout the addition of calcium, phosphate and magnesium. The therapyconsists of contacting the lung or nasal cells with a therapeuticallyeffective amount of the lung surfactant enhancer (inhaled sodiumpyruvate formula with calcium, phosphate and magnesium), alone or incombination with inhaled drugs that cause hypoxemia, while enhancing gasexchanges in the lungs. Some inhaled medications reduce the ability ofthe immune system to fight infections, and some reduce the ability oflungs to synthesize lung surfactants, like steroids, thus the additionof the sodium pyruvate, calcium, phosphate and magnesium formula athigher concentrations will reduce the amount of infections bymaintaining a healthier lung environment where Oxygen saturations areincreased. Wherein the drugs are selected form antivirals,antihistamines, antibacterials, antifungal, proteins, steroids,cytokines, nonsteroidal anti-inflammatory agents, antioxidants, insulin,nicotine and anticancer drugs.

As used herein, the following terms have the given meanings: The term“injured cell” as used herein refers to a cell which has some or all ofthe following: (a) injured membranes with insufficient synthesis of lungsurfactants that reduce lung gas exchange, that transport through themembranes is diminished and may result in one or more of the following,an increase in toxins and normal cellular wastes inside the cell and/ora decrease in nutrients and other components necessary for cellularrepair inside the cell, (b) an increase in concentration of oxygenradicals inside the cell because of the decreased ability of the cell toproduce antioxidants and enzymes, and (c) damaged DNA, RNA and ribosomeswhich must be repaired or replaced before normal cellular functions canbe resumed.

The term “pharmaceutically acceptable,” such as pharmaceuticallyacceptable carriers, excipients, etc., refers to pharmacologicallyacceptable and substantially non-toxic to the subject to which theparticular compound is administered. The term “pharmaceuticallyacceptable salt” refers to conventional acid-addition salts orbase-addition salts that retain the biological effectiveness andproperties of the compounds of the present invention and are formed fromsuitable non-toxic organic or inorganic acids or organic or inorganicbases. Sample acid-addition salts include those derived from inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and thosederived from organic acids such as p-toluene sulfonic acid, salicylicacid, methane sulfonic acid, oxalic acid, succinic acid, citric acid,malic acid, lactic acid, fumaric acid, and the like. Samplebase-addition salts include those derived from calcium, magnesium,ammonium, potassium, sodium, and quaternary ammonium hydroxides, such asfor example, tetramethylammonium hydroxide. Chemical modification of apharmaceutical compound (i.e., drug) into a salt is a technique wellknown to pharmaceutical chemists to obtain improved physical andchemical stability, hydroscopicity, and solubility of compounds. See,e.g., H. Ansel et. al., Pharmaceutical Dosage Forms and Drug DeliverySystems (6^(th) Ed. 1995) at pp. 196 and 1456-1457.

The term “prodrug” or “precursor” refers to compounds that undergobiotransformation prior to exhibiting their pharmacological effects. Thechemical modification of drugs to overcome pharmaceutical problems hasalso been termed “drug latentiation.” Drug latentiation is the chemicalmodification of a biologically active compound to form a new compound,which upon in vivo enzymatic attack will liberate the parent compound.The chemical alterations of the parent compound are such that the changein physicochemical properties will affect the absorption, distributionand enzymatic metabolism. The definition of drug latentiation has alsobeen extended to include nonenzymic regeneration of the parent compound.Regeneration takes place as a consequence of hydrolytic, dissociative,and other reactions not necessarily enzyme mediated. The terms prodrugs,latentiated drugs, and bio-reversible derivatives are usedinterchangeably. By inference, latentiation implies a time lag elementor time component involved in regenerating the bioactive parent moleculein vivo. The term prodrug is general in that it includes latentiateddrug derivatives as well as those substances, which are converted afteradministration to the actual substance, which combines with receptors.The term 5 prodrug is a generic term for agents, which undergobiotransformation prior to exhibiting their pharmacological actions.

The term “therapeutically effective amount” refers to an amount of atherapeutically effective compound, or a pharmaceutically acceptablesalt thereof, which is effective to treat, prevent, alleviate orameliorate symptoms of a disease. The diseases listed below will causeoxygen saturation levels (_(Sao2)) to fall, is due to low lungsurfactant synthesis and causes Hypoxemia. In smokers 22% suffer fromhypoxemia, and in COPD patients 21% have hypoxemia. The pulmonarydiseases which cause Hypoxemia and are suitable for treatment by thelung surfactant enhancer of the present invention (sodium pyruvate withcalcium, phosphate and magnesium), but are not limited to, acuterespiratory distress syndrome (ARDS), acute lung injury, pulmonaryfibrosis (idiopathic), Bleomycin induced pulmonary fibrosis, mechanicalventilator induced lung injury, lung transplantation-induced acute graftdysfunction and bronchiolitis obliterans after lung transplantation,bronchial asthma, acute bronchitis, emphysema, chronic obstructiveemphysema, chronic obstructive pulmonary disease, centrilobularemphysema, panacinar emphysema, chronic obstructive bronchitis, smoker'sdisease, reactive airway disease, cystic fibrosis, black lung disease,bronchiectasis, acquired bronchiectasis, kartaagener's 25 syndrome,atelectasis, acute atelectasis, chronic acelectasis, pneumonia,essential thrombocythemia, legionnaire's disease, psittacosis,fibrogenic dust disease, hypersensitivity diseases of the lung,idiopathic infiltrative diseases of the lungs, chronic obstructivepulmonary disorder, adult respiratory distress syndrome, pulmonarytumors, pulmonary hypertension, and diseases caused by organic dust,cyanide poisoning, nicotine, insulin, irritant gases, Alzheimer's, nasaldiseases like allergic rhinitis, sinusitis and chemicals like Cyanide,ozone, lung or sinus infections, inhaled cancer drugs or inhaled drugs,cancer, sleep apnea, and Migraines. Preferred disease states are cysticfibrosis, bronchial asthma, allergic rhinitis, sinusitis, Bleomycin(doxorubicin) injury, chronic obstructive pulmonary disease,interstitial lung disease, lung cancer and migraines.

The pulmonary tumors suitable for treatment by the surfactant enhancerof the present invention include, but are not limited to, epidermoid(squamous cell) carcinoma, small cell (oat cell) carcinoma,adenocarcinoma, and large cell (anaplastic) carcinoma.

The surfactant enhancers in the present invention are the pyruvates andpyruvate precursors with the addition of calcium, phosphate andmagnesium. Non-limiting illustrative examples of pyruvates includepyruvic acid, sodium pyruvate, potassium pyruvate, magnesium pyruvate,calcium pyruvate, zinc pyruvate, manganese pyruvate, aluminum pyruvate,ammonium pyruvate, lithium pyruvate, and mixtures thereof. Non-limitingillustrative examples of pyruvate precursors include ethyl pyruvate,methyl pyruvate, pyruvyl-glycine, pyruvyl-alanine, pyruvyl-cysteine,pyruvyl-leucine, pyruvyl-valine, pyruvyl-isoleucine,pyruvyl-phenylalanine, pyruvamide, salts of pyruvic acid, and mixturesthereof, with calcium, phosphate and magnesium.

The amount of the surfactant enhancer present in the therapeuticcompositions of the present invention is a therapeutically effectiveamount. A therapeutically effective amount of the surfactant enhancer isthat amount of the surfactant enhancer necessary to increase thesynthesis of lung phospholipids to treat Hypoxemia. The exact amount ofsurfactant enhancer is a matter of preference subject to such factors asthe type of surfactant enhancer being employed, the type of conditionbeing treated as well as the other ingredients in the composition. Theexact amount of surfactant enhancer will also be determined by whetherthe pulmonary disease is infected or uninfected. In general, the dosageof the surfactant enhancer may range from about 0.0001 mg to about 1gram, preferably from about 0.001 mg to about 0.8 gram, and morepreferably from about 0.01 mg to about 0.6 gram.

In many cases, pulmonary diseases produce infections that thesesurfactant enhancers can treat. Such infections may be bacterial, viral,or fungal. The surfactant enhancer may be inhaled first to regulateinflammatory agents followed by inhalation or oral administration of atherapeutic agent. The therapeutic agent may be administered prior to,concomitantly with, or after administration of the inflammatoryregulator. The therapeutic agent may be selected from the groupconsisting of antibacterials, antivirals, antifungals, antitumors,antihistamines, proteins, enzymes, hormones, nonsteroidalanti-inflammatories, cytokines, nicotine, insulin, and steroids.

The antibacterial agents which may be employed in the therapeuticcompositions may be selected from a wide variety of water-soluble andwater-insoluble drugs, and their acid addition or metallic salts, usefulfor treating pulmonary diseases. Both organic and inorganic salts may beused provided the antibacterial agent maintains 15 its medicament value.The antibacterial agents may be selected from a wide range oftherapeutic agents and mixtures of therapeutic agents, which may beadministered in sustained release or prolonged action form. Nonlimitingillustrative specific examples of antibacterial agents include bismuthcontaining compounds, sulfonamides; nitrofurans, metronidazole,tinidazole, nimorazole, benzoic acid; aminoglycosides, macrolides,penicillin's, polypeptides, tetracyclines, cephalosporins,chloramphenicol, and clindamycin. Preferably, the antibacterial agent isselected from the group consisting of bismuth containing compounds, suchas, without limitation, bismuth aluminate, bismuth subcitrate, bismuthsubgallate, bismuth subsalicylate, and mixtures thereof; thesulfonamides; the nitrofurans, such as nitrofurazone, nitrofurantoin,and furazolidone; and miscellaneous antibacterials such asmetronidazole, tinidazole, nimorazole, and benzoic acid; andantibiotics, including the aminoglycosides, such as gentamycin,neomycin, kanamycin, and streptomycin; the macrolides, such aserythromycin, clindamycin, and rifamycin; the penicillin's, such aspenicillin G, penicillin V, Ampicillin and amoxicillin; thepolypeptides, such as bacitracin and polymyxin; the tetracyclines, suchas tetracycline, chlortetracycline, oxytetracycline, and doxycycline;the cephalosporins, such as cephalexin and cephalothin; andmiscellaneous antibiotics, such as chloramphenicol, and clindamycin.More preferably, the antibacterial agent is selected from the groupconsisting of bismuth aluminate, bismuth subcitrate, bismuth subgallate,bismuth subsalicylate, sulfonamides, nitrofurazone, nitrofurantoin,furazolidone, metronidazole, tinidazole, nimorazole, benzoic acid,gentamycin, neomycin, kanamycin, streptomycin, erythromycin,clindamycin, rifamycin, penicillin G, penicillin V, Ampicillinamoxicillin, bacitracin, polymyxin, tetracycline, chlortetracycline,oxytetracycline, doxycycline, cephalexin, cephalothin, chloramphenicol,clindamycin, Bactorban (Mupirocin), Tobramycin, Pentamidine isethionate,Vancomycin, benzalkonium chloride.

The amount of antibacterial agent which may be employed in thetherapeutic compositions of the present invention may vary dependingupon the therapeutic dosage recommended or permitted for the particularantibacterial agent. In general, the amount of antibacterial agentpresent is the ordinary dosage required to obtain the desired result.Such dosages are known to the skilled practitioner in the medical 15arts and are not a part of the present invention. In a preferredembodiment, the antibacterial agent in the therapeutic composition ispresent in an amount from about 0.01% to about 10%, preferably fromabout 0.1% to about 5%, and more preferably from about 1% to about 3%,by weight.

The antiviral agents which may be employed in the therapeuticcompositions may be selected from a wide variety of water-soluble andwater-insoluble drugs, and their acid addition or metallic salts, usefulfor treating pulmonary diseases. Both organic and inorganic salts may beused provided the antiviral agent maintains its medicament value. Theantiviral agents may be selected from a wide range of therapeutic agentsand mixtures of therapeutic agents, which may be administered insustained release or prolonged action form. Nonlimiting illustrativecategories of such antiviral agents include RNA synthesis inhibitors,protein synthesis inhibitors, immune-stimulating agents, proteaseinhibitors, and cytokines. Nonlimiting illustrative specific examples ofsuch antiviral agents include the following medicaments. Acyclovir withinhibitory activity against human herpes viruses including herpessimplex types 1 (HSV-1) and 2 (HSV-2), varicella-zoster virus (VZV),Epstein-Barr virus (EBV), and cytomegalovirus (CMV). Foscarnet sodium isan organic analogue of inorganic pyrophosphate that inhibits replicationof all known herpes viruses in vitro including cytomegalovirus (CMV),herpes simplex virus types 1 and 2 (HSV-1, HSV-2), human herpes virus 6(HHV-6), Epstein-Barr virus (EBV), and varicellazoster virus (VZV).

Ribavirin has antiviral inhibitory activity in vitro against respiratorysyncytial virus, influenza virus, and herpes simplex virus. Vidarabinepossesses in vitro and in vivo antiviral activity against Herpes simplexvirus types 1 and 2 (HSV-1 and HSV-2), and in vitro activity againstvaricella-zoster virus (VZV). Ganciclovir inhibits replication of herpesviruses both in vitro and in vivo. Sensitive human viruses includecytomegalovirus (CMV), herpes simplex virus-1 and -2 (HSV-1, HSV-2),Epstein-Barr virus (EBV), and varicella zoster virus (VZV). Zidovudineis an inhibitor of the in vitro replication of some retrovirusesincluding HIV (also known as HTLV III, LAV, or ARV). Phenol (carbolicacid) is a topical antiviral, anesthetic, antiseptic, and antipruriticdrug. Amantadine hydrochloride (1-adamantanamine hydrochloride,SYMMETREL®) has pharmacological actions as both an anti-Parkinson and anantiviral drug against influenza A. Interferon □-n3 (human leukocytederived, ALFERON®) □ proteins for use by injection. Interferons arenaturally occurring proteins with both antiviral and antiproliferativeproperties. Interferon □-2a (recombinant, ROFERON-A®). The mechanism bywhich Interferon □-2a, recombinant, exerts antitumor or antiviralactivity is not clearly understood. 20 Oseltamivir((3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexenel-carboxylicacid ethyl ester, TAMIFLU®) is a is an antiviral drug that is used inthe treatment and prophylaxis of both influenza virus A and Influenzavirus B. Zanamivir. Preferred antiviral agents to be employed may beselected from the group consisting of acyclovir, foscarnet sodium,Ribavirin, vidarabine, Ganciclovir sodium, zidovudine, phenol,amantadine hydrochloride, and interferon alpha-n3, interferon-2a, andOseltamivir. In a preferred embodiment, the antiviral agent is selectedfrom the group consisting of acyclovir, foscarnet sodium, Zanamivir,Ribavirin, vidarabine, valacydvir, famiclour, Tenofovir Viread andGanciclovir sodium. In a more preferred embodiment, the antiviral agentis acyclovir.

The amount of antiviral agent which may be employed in the therapeuticcompositions of the present invention may vary depending upon thetherapeutic dosage recommended or permitted for the particular antiviralagent. In general, the amount of antiviral agent present is the ordinarydosage required to obtain the desired result. Such dosages are known tothe skilled practitioner in the medical arts and are not a part of thepresent invention. In a preferred embodiment, the antiviral agent in thetherapeutic composition is present in an amount from about 0.1% to about20%, preferably from about 1% to about 10%, and more preferably fromabout 2% to about 7%, by weight.

The antifungal agents which may be employed in the therapeuticcompositions may be selected from a wide variety of water-soluble andwater-insoluble drugs, and their acid addition or metallic salts, usefulfor treating pulmonary diseases. Both organic and inorganic salts may beused provided the antifungal agent maintains its medicament value. Theantifungal agents may be selected from a wide range of therapeuticagents and mixtures of therapeutic agents, which may be administered in15 sustained release or prolonged action form. Nonlimiting illustrativespecific examples of antifungal agents include the followingmedicaments: miconazole, clotrimazole, tioconazole, terconazole,povidone-iodine, and butoconazole. Other antifungal agents are lacticacid and sorbic acid. Preferred antifungal agents are miconazole andclotrimazole. The amount of antifungal agent, which may be employed inthe therapeutic compositions of the present invention may vary dependingupon the therapeutic dosage recommended or permitted for the particularantifungal agent. In general, the amount of antifungal agent present isthe ordinary dosage required to obtain the desired result. Such dosagesare known to the skilled practitioner in the medical arts and are not apart of the present invention. In a preferred embodiment, the antifungalagent in the therapeutic composition is present in an amount from about0.05% to about 10%, preferably from about 0.1% to about 5%, and morepreferably from about 0.2% to about 4%, by weight.

The antitumor agents which may be employed in the therapeuticcompositions may be selected from a wide variety of water-soluble andwater-insoluble drugs, and their acid addition or metallic salts, usefulfor treating pulmonary diseases. Both organic and inorganic salts may beused provided the antitumor agent maintains its medicament value. Theantitumor agents may be selected from a wide range of therapeutic agentsand mixtures of therapeutic agents, which may be administered insustained release or prolonged action form. Nonlimiting illustrativespecific examples include anti-metabolites, antibiotics, plant products,hormones, and other miscellaneous chemotherapeutic agents. Chemicallyreactive drugs having nonspecific action include alkylating agents andN-alkyl-N-nitroso compounds. Examples of alkylating agents includenitrogen mustards, aziridines (ethylenimines), sulfonic acid esters, andepoxides. Anti-metabolites are compounds that interfere with theformation or utilization of a normal cellular metabolite and includeamino acid antagonists, vitamin and coenzyme antagonists, andantagonists of metabolites involved in nucleic acid synthesis such asglutamine antagonists, folic acid antagonists, pyrimidine antagonists,and purine antagonists. Antibiotics are compounds produced bymicroorganisms that have the ability to inhibit the growth of otherorganisms and include actinomycins and related antibiotics, glutarimideantibiotics, sarkomycin, fumagillin, streptonigrin, tenuazonic acid,actinogan, peptinogan, and anthracyclic antibiotics such as doxorubicin.Plant products include colchicine, podophyllotoxin, and vinca alkaloids.Hormones include those steroids used in breast and prostate cancer andcorticosteroids used in leukemia and lymphomas. Other miscellaneouschemotherapeutic agents include urethane, hydroxyurea, and relatedcompounds; thiosemicarbazones and related compounds; phthalanilide andrelated compounds; and triazene's and hydrazines, 3Bromopyruvate,2-Deoxy-D glucose, Dichloroacetic acid. The anticancer agent may also bea monoclonal antibody or the use of X-rays. In a preferred embodiment,the anticancer agent is an antibiotic. In a more preferred embodiment,the anticancer agent is doxorubicin. In a most preferred embodiment, theanticancer agent is doxorubicin. Lung Cancer—Medications Chemotherapy iscalled a systemic treatment because the medicines enter yourbloodstream, travel through your body, and kill cancer cells both insideand outside the lung area. Some chemotherapy drugs are taken by mouth(orally), while others are injected into a vein (intravenous, or IV).Some of the more common chemotherapy medicines used for lung cancerincludes the following: Bevacizumab, Carboplatin, Cisplatin, Crizotinib,Docetaxel, Erlotinib, Etoposide, Gemcitabine, Irinotecan, Paclitaxel,Pemetrexed Vinorelbine.

Most chemotherapy causes some side effects, including destruction ofmitochondria which causes an insufficient synthesis of lung surfactantsthat lead to hypoxemia and reduces the ability of cancer cells toundergo Apoptosis.

The amount of antitumor agent, which may be employed in the therapeuticcompositions of the present invention may vary depending upon thetherapeutic dosage recommended or permitted for the particular antitumoragent. In general, the amount of antitumor agent present is the ordinarydosage required to obtain the desired result. Such dosages are known tothe skilled practitioner in the medical arts and are not a part of thepresent invention. In a preferred embodiment, the antitumor agent in thetherapeutic composition is present in an amount from about 1% to about50%, preferably from about 10% to about 30%, and more preferably fromabout 20% to about 25%, by weight. The carrier composition is selectedfrom the group consisting of tablets, capsules, liquids, isotonicliquids, isotonic media, enteric tablets and capsules, parenteral,topicals, creams, gels, ointments, chewing gums, confections and thelike. The favored method of delivery is through inhalation by mouth orsinuses.

Obviously, numerous modifications and variations of the presentinvention are possible in the light of the above teachings and theinvention is not limited to the examples herein. It is thereforeunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described herein.Throughout this application, various publications have been referenced.The disclosures in these publications are incorporated herein byreference in order to more fully describe the state of the art.

The compounds of the present invention can be prepared according to theexamples set out below. The examples are presented for purposes ofdemonstrating, but not 30 limiting, the preparation of the compounds andcompositions of this invention.

Example 1 Sodium Pyruvate Formula Containing Calcium, Phosphate andMagnesium

All previous studies using pyruvate to treat Allergic Rhinitis,Asthmatic and COPD patients used only the sodium salt form of pyruvicacid in saline. The drug products that were tested in the six Phase I/IIclinical trial were differing concentrations of sodium pyruvatedissolved in 0.9% sodium chloride solution (Saline). These drug productscontained 0.5 mM, 1.5 mM, or 5.0 mM of sodium pyruvate in physiologicalsaline. They were administered to normal volunteers and COPD andasthmatics by inhalation therapy. Even though other salts of pyruvicacid like calcium, potassium or zinc etc. have been suggested, no one todate has evaluated the different salts individually or in combinationfor their ability to enhance lung function and reduce lung tightness dueto low surfactant production and help in mucus removal that can inhibitdrug efficacy. Removal of mucus will increase the efficacy of thepyruvate membrane transport system. Various sodium pyruvate solutionswere evaluated in the lungs for their ability to enhance FEV1 values andreduce coughing, and lung tightness. 5 ml 0.5 mM solutions to 5 mMsolutions of sodium pyruvate in saline were evaluated in Asthmatic andCOPD patients and the 5 ml of the 0.5 mM solution produced the bestresults in increasing FEV1 values of over 12% and reducing nitric oxideby 19.2%.

The products that were tested in the clinical trials were differingconcentrations of sodium pyruvate dissolved in 0.9% sodium chloridesolution. These drug products contained 0.5 mM, 1.5 mM, or 5.0 mM (275,825, and 2750 μg) of sodium pyruvate, respectively delivered per doseper day. Of these, a 5 mL dose of 0.5 mM sodium pyruvate dissolved in0.9% sodium chloride solution proved to be the concentration and dosageof choice in past clinical studies. Various investigators including Katzand Martin discovered that the higher concentrations of sodium pyruvate1.5 mM, or 5.0 mM (825, and 2750 μg) in saline did not increase FEV1values.

Blood levels of the various salts mg/liter are 3220 mg for Sodium, 200mg for potassium, 27 mg for magnesium, 70 mg for calcium, 1.1 mg forzinc, 0.02 mg for manganese, 6 mg for lithium, 0.03 mg for aluminum,0.06 mg for ammonium and 0.36 mg for phosphate. To evaluate theirritation or toxicity levels of these elements 5 mls of 0.5 mM solutionof each salt of pyruvate, was tested against the standard 5 mls of the0.5 mM solution of sodium pyruvate that was shown to be non-toxic inhumans and animal studies. In fact, in rat studies, 100× concentrationsof the 5 mM sodium pyruvate was tested and shown not to have anyirritation or toxicity. Using 5 mls of a 0.5 mM pyruvate inhalationsolution of each salt in COPD and asthmatic patients, the use ofpotassium pyruvate, magnesium pyruvate, calcium pyruvate, zinc pyruvate,manganese pyruvate, lithium pyruvate, aluminum pyruvate, and ammoniumpyruvate were evaluated. Potassium pyruvate, produced lower FEV1 resultsin COPD patients as the sodium pyruvate solution did (FEV1 of 12% orhigher). The calcium pyruvate and magnesium pyruvate increased FEV1values to 10%. The zinc pyruvate, manganese pyruvate, aluminum pyruvate,ammonium pyruvate, and lithium pyruvate did produce slight increases inFEV1 of around 4-6% but did not reduce nitric oxide and did not achievethe results that sodium pyruvate produced, and they were irritating. Thezinc pyruvate increased nitric oxide levels by 10% instead of reducingit, acting in the opposite direction that sodium pyruvate did. See tableI. A metal taste to these solutions was described by the inhalers. Theamount of the salts delivered in the 5 ml's of the 0.5 mM pyruvatesolutions were compared to the amounts of the salts in 5 ml's of humanblood. The sodium, potassium, and calcium, pyruvates were all underamounts found in human blood. The delivered zinc in this solution (5 mlof a 0.5 mM) was 12× blood levels, the 20 magnesium was 4× blood levels,the manganese was 370× blood levels, aluminum was 61× times bloodlevels, the ammonium was 53× times blood levels, and lithium was 5×blood levels. These solutions were also evaluated in the nasal cavitiesand were less irritating than in the lungs except, the ammonium andlithium pyruvate was even more irritating than its use in the lungs. Theuse of these elements at these levels proved that one cannot assume thatall the salts of pyruvate are equal in efficacy or in irritation whencompared to the sodium salt see table I. Even though the use of some ofthese salts of pyruvic acid showed similar FEV1 results, and the othersdid not. The use of some of these salts over time may have a negativeeffect. The sodium salt of pyruvate when tested at higher levels inhumans like the 5 ml of the 5 mM was 59 times lower than sodium in 5ml's of blood, the calcium was 1.5× times lower, the potassium was 3.2×times lower than 5 ml's of blood, thus they were well within the safelevels needed to deliver the pyruvate. In small doses the salts of zinc,manganese can be used to increase and up regulate the immune systemcytokines to fight infections, rather than their use as ananti-inflammatory agent that increases lung functions and FEV1 values.Lithium pyruvate had the unexpected result of acting as a bronchialdilator whereas the other salts were weak or nonexistent as a bronchialdilator.

When the sodium pyruvate solution (0.5 mM, 0.274 mg) was balanced withthe salt of calcium pyruvate or calcium chloride to the concentrationsof the salts found in blood (formula was 97% sodium pyruvate, 3% calciumpyruvate or 3% calcium chloride), it produced equal results in FEV1values when compared to the original sodium pyruvate formula tested inthe COPD patients. This formula can also be made by adding 3% calciumphosphate or dicalcium phosphate to the standard 0.5 mM to 30 mM sodiumpyruvate saline solution see Table I.

The sodium pyruvate formula with the calcium, phosphate and magnesiumwas significantly superior to any other formula that only delivercalcium with or without the phosphate or magnesium see table I-II. Inprevious studies, sodium pyruvate solutions of 5 to 20 mM did notincrease FEV1 values and did increase nitric oxide levels significantlyto 19%. The FEV1 values increase to 16% for the sodium pyruvate calcium,phosphate and magnesium formula (20 mM solution) and nitric oxidedecreased by 70%, far different results than the 5-20 mM straight sodiumpyruvate formula without the calcium, phosphate and magnesium, see tableII. It was also reported by the patients that the sodium pyruvatecalcium, phosphate and magnesium formula was the best formula to reducelung tightness coughing and mucus. The addition of all the other saltsof pyruvate including zinc, lithium, magnesium, aluminum, ammonium, ormanganese even at blood levels concentrations individually, gave theformula a metal taste and was not preferred by 25 the patients thatinhaled it, see table II.

TABLE I Comparison of various inhaled salts of pyruvate in 5 ml's of a0.5 mM solution in patients with lung diseases including COPD. Overallrating was 1-10 with 1 being the most negative and 10 being the bestresult Percentage decrease or Relief of Percentage Various Salts ofIncreased increase of congestion, Increase in Overall pyruvate in inFEV-1% Nitric Oxide coughing and SaO2 over Rating physiological salinelung function over baseline Irritation lung tightness baseline 1-10Sodium 13.0 −19.0 none 5   0.5 8 Calcium 10.0 −18 None 5 no 7 Potassium8.0 −14 None 5 no 7 Magnesium 12.0 −2.0 None 6 no 7 Zinc 8.0 +10 Yes 4No 4 Manganese 3.0 −2.0 Yes 4 No 3 Lithium 1.0 +6.0 Yes 2 No 2 Aluminum0 +8.0 Yes 1 No 3 Ammonium 0 +5.0 Yes 1 No 1 Potassium Phosphate 0 0Slight 4 No 3 sodium pyruvate & 12.2 −18 None 6 No 8 calcium pyruvatesodium pyruvate & 11.8 −14 None 6 No 8 calcium pyruvate & magnesiumcalcium & Phosphate & 0 0 None 1 No 2 magnesium Sodium Pyruvate & 16 −28None 9 5% 10 calcium &Phosphate &magnesium physiological 0 0 None 0 0 5Saline 0.9% Pyruvyl-cysteine 11 0 None 5 0 8 N-acetylcysteine 6 0 None 80 7

TABLE II Comparison of various inhaled salts of pyruvate in 5 ml's of a5 mM solution in patients with lung diseases including COPD. Overallrating was 1-10 with 1 being the most negative and 10 being the bestresult Relief of Percentage congestion, Percentage increase of coughingIncrease in Overall Various Salts of Increased Nitric Oxide and lungSaO2 over Rating pyruvate in saline in FEV-1% over baseline Irritationtightness baseline 1-10 Sodium 2.0 19.0 none 5 1 8 Calcium 1.0 17.0 None5 1 7 Potassium 2.1 25.0 None 5 no 7 Magnesium 2.0 5.1 None 6 no 7 Zinc1.0 22.0 Yes 4 No 3 Manganese 3.0 25.0 Yes 4 No 3 Lithium 1.0 28.0 Yes 2No 2 Aluminum 0 15.0 Yes 1 No 4 Ammonium 0 35.0 Yes 1 No 1 PotassiumPhosphate 0 0 Slight 4 No 3 sodium & calcium 2.2 16 None 6 No 8 pyruvatesodium & calcium 3.4 15 None 6 No 8 pyruvate & magnesium calcium &Phosphate & 0 0 None 1 No 2 magnesium Sodium Pyruvate & 16 70 None 9 5%10 calcium & Phosphate & magnesium Physiological 0 0 0 0 0 5 Saline 0.9%Pyruvyl-cysteine 5 1 Slight 8 0 8 N-acetylcysteine 2 1 yes 7 0 7

Example II Effect of CO2 Concentration on Phospholipid Metabolism in theIsolated Perfused Rat Lung

In Hypoxemia CO2 levels rise as SaO₂ levels decline. Studies have beencarried out on the incorporation of [U-(14)C]glucose, [2 (14)C]pyruvate,[2-(14)C]acetate, and [1-(14)C]-palmitate into the phospholipids of theisolated perfused rat lung in the presence of either 6 or 45 mm totalCO(2) concentration in the perfusion medium. Incorporation of[U-(14)C]glucose into total phospholipid and into thephosphatidylcholine fraction was increased 19-53% over the 2-hrperfusion period in lungs perfused with medium containing 45 as comparedwith 6 mm CO(2). The incorporation of [2-(14)C]acetate,[2-(14)C]-pyruvate, and [1(14)C]palmitate was not affected by the changein medium CO(2) concentration and incorporation of [U-(14)C] pyruvateinto total phospholipid and into the phosphatidylcholine fraction wasincreased 1-3% over the 2-hr perfusion period in lungs perfused.Increased incorporation of [1-(14)C]glucose combined with a shift towardgreater incorporation into the fatty acids of the phosphatidylcholinefraction produced a maximum increase of 90% in [U-(14)C]glucoseincorporation into the fatty acids of phosphatidylcholine after 2 hr ofperfusion in the presence of medium containing 45 mm CO(2) as comparedwith 6 mm CO(2). 45 mm CO2 increases hypoxemia. The increase in mediumCO(2) concentration produced as much as a 150% increase in[U-(14)C]glucose incorporation into palmitate derived from thephosphatidylcholine fraction. The results provide evidence that glucosefunctions as an important precursor of palmitate in thephosphatidylcholine fraction of lung phospholipids and that the CO(2)concentration of the perfusion medium affects the incorporation ofglucose into palmitate, whereas in hypoxemia states sodium pyruvate isnot incorporated into lung surfactants.

The combination of sodium pyruvate and calcium, phosphate and magnesiumwas synergistic in its ability to increase the incorporation of pyruvateinto lung surfactant phospholipids. It enhanced surfactant production,pyruvate uptake and mucus removal. The production of phospholipids thatmake up the lung surfactants, needed to enhance alveoli function, needtrace minerals and salts to be synthesized. The components of pulmonarysurfactant are synthesized in the Golgi apparatus of the endoplasmicreticulum of the type II alveolar cell and the secretion is induced byendoplasmic reticulum Ca2 ATPase. The addition of calcium, phosphate andmagnesium, not zinc or the other salts of pyruvate, enhanced theproduction of the surfactants. In previous studies with rat lungs,[2-(14) C]-pyruvate was not incorporated into lung surfactants underhigh CO2 levels which produce hypoxemia. In isolated perfused rat lungs,using [2-(14)C] labeled pyruvate; lung surfactant analysis clearlyshowed that the sodium pyruvate calcium, phosphate and magnesium formulaincreased the production of surfactants over all other formulations withjust sodium pyruvate in saline alone. It was also discovered that 50% ofthe radioactive pyruvate from this formula was incorporated intophosphatidylcholine the main lung surfactant with 45 mm CO2concentrations. In short, calcium, phosphate and magnesium is needed bythe enzyme systems to synthesize lung surfactants, while phosphateprovides some of the building components needed to make surfactants, orto increase the synthesis of surfactants and, thus decrease hypoxemia.Inhalation studies with just [2-(14)C] labeled sodium pyruvate withoutcalcium, phosphate and magnesium, showed that pyruvate was converted inthe lungs or sinuses to acetate and carbon dioxide and higher levels ofpyruvate increased the synthesis of nitric oxide and was notincorporated into synthesized phospholipids. In patients with excessmucus, the formula of sodium pyruvate and calcium, phosphate andmagnesium helped facilitate mucus removal, by providing the energy andnutrients needed by the cilia in the nasal and lung passages to removethe mucus. This formula was evaluated in patients with excess mucus. Seetables I-III.

TABLE III Comparison of various 5 ml's of 5 mM sodium pyruvate salineformulas in patients with hypoxemia with and without lung diseases.Overall rating was 1-10 with 1 being the most negative and 10 being thebest result Relief of Percentage Relief of coughing Percentage increaseof Congestion percentage Percentage Increase in Nitric and lung decreaseIncrease in Overall Various Salts of FEV-1 over Oxide over tightness infour SaO2 over Rating pyruvate in saline baseline baseline 1-10 hoursbaseline 1-10 Sodium pyruvate 4.0 18.0%  5 15 0 7 sodium pyruvate & 4.019.0%  5 16 0 7 calcium pyruvate sodium pyruvate & 3.0 18% 5 22 0 7calcium & phosphate calcium & Phosphate & 0 0 1 1 0 3 magnesium SodiumPyruvate & 15.2 80% 9 48 6% 10 calcium & Phosphate & magnesiumPhysiological Saline 0  2% 5 2 0 3 Sodium Pyruvate & 14.9 112%  9 44 5%9 calcium & Phosphate & Magnesium + N-acetylcysteine Sodium pyruvate + 415% 7 12 1 8 N-Acetylcysteine

Example III Inhalation Formulation

Numerous inhaled formulas have been used alone or as part of a solutionto carry drugs into the lungs to treat lung diseases, cancer, infectionsetc. To dated, none of these FDA approved inhalation formulas, have beenshown to enhance the synthesis of lung surfactants, treat hypoxemia byincreasing _(SaO2) levels, while increasing the synthesis of nitricoxide. We assessed the following formulas, physiological saline,lactated Ringers, acetated Ringers, ethyl pyruvate Ringers, Phosphatebuffered saline, TRIS buffered saline, Hepes buffered saline, Citratesaline, Hanks balanced salt solution, Eagles balanced salt solution,Geys balanced slat solution, and Earls balanced salt solution. All theseformulas are the same in that they all use sodium chloride at 0.8-0.9grams per liter or higher and when tested in patients with various sinusor lung diseases including COPD patients with hypoxemia, none of theseformula increased _(SaO2) levels or decrease lung tightness, coughing orincrease lung capacity. None of these formulae have all of the correctingredients or the correct ratios of Sodium pyruvate, calcium,phosphate, or magnesium. Most of these formulas also contain glucosethat inhibits the incorporation of pyruvate into phospholipids.

Inhalation of sea salt aerosol is clinically proven and cleans therespiratory system of the body and speeds up the elimination of toxins.Salt therapy for Chronic Obstructive Pulmonary Disease (COPD) is anatural and effective treatment for a number of health issues, includingemphysema and bronchitis that relate to the lungs and that are groupedtogether under the banner of Chronic Obstructive Pulmonary Disease. Salttherapy is 100% natural, safe and drug-free, providing effectivelong-term relief. Sodium and chloride are the most abundant ions in seasalt, representing about 33 and 50.9 percent of total minerals,respectively. Potassium is another important macro-mineral that workswith chloride to help regulate acid levels in your body. Sea saltcontains also contains Calcium and magnesium. Sea salt can also containnumerous trace elements. Trace minerals you may find in sea saltinclude, bromine, boron, zinc, iron, manganese, copper and silicon.What's missing in sea salt is the correct composition of ingredients,with the correct concentrations and ratios of sodium pyruvate, calcium,magnesium and phosphate. In sea salt phosphate is 125 times lower thanblood levels and calcium is 50% lower than blood levels. When tested byitself, in hundreds of published clinical studies, or with the additionof sodium pyruvate, sea salt did not increase the synthesis of lungphospholipids, nor decrease hypoxemia, decrease lung tightness orincrease lung capacity or _(SaO2) levels. When the correct compositionof ingredients with the correct concentrations and ratios of sodiumpyruvate, calcium, phosphate, and magnesium were added to sea salt, thesynthesis of lung surfactants increased, lung capacity increased, lungtightness decreased and hypoxemia decreased.

20 mM Sodium Pyruvate Formula for Inhalation:

The best formula we tested was

To one liter of saline, 0.65% Sodium Chloride (contains 6.5 grams ofNaCl), add 0.22% (2.2 grams) of sodium pyruvate, 0.15% calcium chloride(0.15 grams), 0.11% of magnesium chloride (0.11 grams), 0.03% potassiumphosphate (0.03 grams). Tissue culture studies with lung cells haveshown that adding to much Chloride or sodium will injure those cells. A20 mM formula would contain 2.2 grams of sodium pyruvate. And a 0.5 mMsolution would contain 0.055 grams of sodium pyruvate. A secondapproached tried with the same effect was to first have the patientsinhale physiological saline with 0.15% calcium chloride (0.15 grams),0.11% of magnesium chloride (0.1 grams), 0.03% potassium phosphate (0.03grams) followed by the inhalation of sodium pyruvate in physiologicalsaline one hour later. This formula has many modifications to deliverthe correct amount of pyruvate, calcium, phosphate and magnesium.Phosphate can be delivered as calcium phosphate, dicalcium phosphate,potassium phosphate monobasic, dipotassium phosphate, tri potassiumphosphate, magnesium phosphate, zinc phosphate and sodium phosphatedibasic. In certain liquid inhalation formulations, dicalcium phosphate,is not as soluble as potassium phosphate, which can substitute for it inany inhaled formulation. Calcium can be delivered as calcium chloride,calcium carbonate, calcium acetate, calcium citrate, calcium lactate,and calcium sulfate and calcium pyruvate. Pyruvate can be delivered inmany salt forms. Sodium, Potassium, calcium, magnesium and the othersalts etc. Magnesium can be delivered as magnesium chloride, magnesiumphosphate, magnesium bicarbonate or magnesium sulfate. The PH should beadjusted to 7.4 with sodium hydroxide. Calcium and magnesium are neededfor lung enzymes to make phospholipids and phosphate and pyruvate areused as an ingredient in phospholipids. Magnesium is also needed formitochondrial membrane stability and for the production of ATP. Withoutthe addition of calcium, phosphate or magnesium, pyruvate is convertedin the lungs to water, CO2 and acetate. See table III.

Example IV: Inhaled Sodium Pyruvate with and without Calcium, Phosphateand Magnesium. _(SaO2) Pilot Study in Subjects with Chronic HypoxemiaDue to Insufficient Synthesis of Lung Surfactants in Patients with LungDiseases, Including Asthmatics, Patients with Interstitial Lung Disease,and COPD Patients

A total of five (5) subjects diagnosed with Severe COPD (chronicbronchitis or emphysema) and requiring supplemental oxygen at rest wereenrolled in this study at the University of Connecticut. Each subjectreceived a single inhalation dose of either 0.5 mM sodium pyruvate, 5.0mM sodium pyruvate or 0.9% sodium chloride at each Study Visit. The dosewas administered in a blinded cross-over manner at 1 week intervals;such that all subjects received each study compound. Safety andtherapeutic efficacy were evaluated by the following measurements:spirometry, expired breath NO level, _(SaO2), vital signs, and follow-uptelephone interviews.

The study was conducted in four visits: a Screening Visit and StudyVisits 1-3. The effect of the inhalation of a single dose of sodiumpyruvate (0.5 mM and 5.0 mM) or placebo (0.9% sodium chloride) wasstudied in a double-blind protocol. The primary efficacy outcomeobjective was the _(SaO2) levels for all subjects. In addition, COPDsubjects were evaluated by lung function (FEV₁ and PEF) and expiredbreath NO levels obtained just prior to and then at 60 minutes and at 3hours in the second study, following the administration of theparticular sodium pyruvate dose. Since safety has been demonstrated inprevious studies, only vital signs were monitored prior to, and postinhalation of, sodium pyruvate.

Pulse oximetry is a simple, cheap, and noninvasive procedure used tomeasure the level of oxygen (or oxygen saturation) in the blood. Oxygensaturation should always be above 95 percent. However, oxygen saturationmay be lower if you have a respiratory disease or congenital heartdisease. You can measure the blood's percentage of oxygen saturationusing a pulse oximeter, a clip-like sensor device that is placed on yourfinger. A pulse oximeter may also be used to assess, whether lungmedications are working effectively, and to determine patient toleranceto increased activity levels, or patients that suffer from sleep apneaor have a serious medical condition, such as heart attack, congestiveheart failure, chronic obstructive pulmonary disease (COPD), anemia,lung cancer, asthma, or pneumonia. Oximeters use the light absorptivecharacteristics of hemoglobin and the pulsating nature of blood flow inthe arteries to measure the level of oxygen in the body. Your oxygensaturation level and pulse rate are displayed in seconds on a lighteddisplay screen. A range of 95% to 100% is generally considered normal.If your oxygen level drops below 85%, you should seek medical attention.

There were no Adverse Events noted in any of the subjects studied. Nophysiological alterations occurred that caused study termination of anyof the participants after the inhalation of sodium pyruvate. Nosignificant change in the FEV₁ or _(SaO2) was observed in any of thesubjects after the inhalation of the 0.5 mM or 5.0 mM sodium pyruvate insaline or physiological saline as compared to the pre inhalation values.Nitric oxide levels were increased by 19% with the 5 mM inhaledsolution. This explains why sodium pyruvate by itself, without thecorrect ratio of calcium, phosphate and magnesium did not increase_(SaO2) levels in patients with severe COPD that have hypoxemia.

Example V

A repeat of this study with 6 patients with various lung and sinusdiseases including moderate COPD patients, interstitial lung disease andhypoxemia, showed an increase in FEV-1, _(SaO2) and no increase level ofNO in the patients treated with both the 0.5 mM or 5.0 mM surfactantenhancer (sodium pyruvate formula with calcium, phosphate andmagnesium). This formula was rated higher than the standard sodiumpyruvate solution without calcium, phosphate and magnesium. See TablesI-III. Both the nasal spray and the nebulized lung solution with thesurfactant enhancer (sodium pyruvate formula with calcium, phosphate andmagnesium) increased Sa02 in patients with COPD Cystic Fibrosis, Asthma,Allergic Rhinitis, Alzheimer's, interstitial lung disease, cancer and inother lung and sinus diseases by an average of 4%. The inhalation of 20mM of the surfactant enhancer increased _(SaO2) by 6% and decreasedcoughing and lung tightness by 40% over the standard sodium pyruvateformula without calcium, phosphate and magnesium. See table IV.

In reviewing the literature, it was found that various salts of chloridehave been used as carriers of various inhalation drugs for the nasalcavity or lungs, because they have provided no clinical effects orefficacy for the treatment of lung diseases. Sodium chloride is mainlyused as nasal or lung moisturizer. All the other salts, calciumchloride, potassium chloride, and magnesium chloride, potassiumphosphate, calcium phosphate, have also been used as carrier vehiclesand moisturizers. They produce no change to FEV-1 or _(SaO2)measurements. It must be noted that there is a difference between peoplewho have transient hypoxemia vs. one that has permanent hypoxemia. Thepatients respond differently to the inhalation of sodium pyruvate byitself without calcium, phosphate and magnesium. Sodium pyruvateformulations both given orally or by inhalation will increase _(SaO2)levels in people without lung injury to the alveoli structure especiallythe mitochondria that can synthesis the phospholipids needed for oxygenexchange and uptake. Transient hypoxemia is a self-correcting effect. Itoccurs in over exercising, mountain climbing etc. In controlledinhalation studies, patients with no lung injuries or disease, showed anincrease of _(SaO2) by an average of 3% after exercising. Patients withlung damage, like in smokers, which have a 50% rate of hypoxemia, didnot show an increase saw levels after inhaling sodium pyruvate withoutcalcium, phosphate and magnesium. See tables I-IV. In patients withinfections, i.e. CF and allergic Rhinitis, Nitric Oxide increase by over400% over base line measurements with the use of the sodium pyruvate,calcium, phosphate and magnesium formula, needed to fight infections andlung cancer (see table IV).

TABLE IV Percentage measurements in patients with permanent hypoxemiaagainst control group without Hypoxemia. 20 mM sodium pyruvate formulawith calcium, phosphate and magnesium were inhaled. Overall rating was1-10 with 1 being the most negative and 10 being the best resultPercentage Lung Percentage Relief of Percentage Percentage tightnessPercentage increase in congestion decrease Increase in Overall VariousLung and Increase in Nitric oxide and lung in coughing SaO2 over Ratingsinus diseases FEV-1 over baseline tightness in 4 hours baseline 1-10Control group 5 4.0 10.0 15.0 12.0 0.5 8 Moderate COPD without HypoxemiaPatients with Hypoxemia 15 moderate COPD 14.0 20.0 28.0 48.0 3.0 7 5Asthmatics 8.0 14.0 25.0 10.0 4.0 7 13 CF 6.0 453.0 42.0 30.0 4.0 10 10Allergic 12.0 43.0 68.0 22.0 5.0 10 Rhinitis and various sinus diseases5 Alzheimer's 12.0 41.0 38.0 14.0 4.5 9 patients 4 Interstitial lung14.0 10.0 19.0 33.0 3.0 9 disease Three patients with 11 422 15 25 4 10lung cancer

Both the nasal spray and the nebulized lung solution with the sodiumpyruvate formula with calcium, phosphate and magnesium, increased Sa02in patients with COPD Cystic Fibrosis, Asthma, Allergic Rhinitis,Alzheimer's, interstitial lung disease and in other lung and sinusdiseases by an average of 4%. The inhalation of the nasal spray 20 mMsodium pyruvate with calcium, phosphate and magnesium was administeredfirst to all patients followed by the inhalation by nebulization of the20 mM sodium pyruvate with calcium, phosphate and magnesium, increased_(SaO2) by 6% and decreased coughing and lung tightness by 40% over thestandard odium pyruvate formula without calcium, phosphate andmagnesium. For the first time a way to increase SaO2 levels inAlzheimer's patients that sodium pyruvate could not do without theaddition of calcium, phosphate and magnesium. The ability to enhance thesynthesis of brain or lung phospholipids had a dramatic effect onAlzheimer's patient's cognitive ability increasing the score to 70%.Aside from Alzheimer's disease, Parkinson's disease is the mostwell-known disease in the neurodegenerative disease group. Parkinson'sdisease (PD) is a chronic and progressive degenerative disease of thebrain that impairs motor control, speech, and other functions. Twopatients suffering from Parkinson were given inhaled lithium pyruvate (1mM solution in the calcium, phosphate, magnesium formula) every day forfive weeks and in week one of treatment the shaking was substantiallyreduced in both patients. Pyruvate is one of major energy carriers inthe brain, it is shown to be protective against damaging consequences ofneurotoxins, such as hydrogen peroxide, glutamate, zinc, andcopper/cysteine. Supplementation of glucose containing culture mediawith energy substrates, plus pyruvate, protected rat primary neuronsfrom degeneration and death caused by A-beta peptides characteristic forAlzheimer's disease. Magnesium pyruvate also worked in these patients.

Example VI Patients with Severe Lung Injury or Mitochondrial Damage orCOPD and Hypoxemia with Reduced Lung Capacity

Total lung capacity is the volume in the lungs at maximal inflation, thesum of VC and RV. RV is the residual volume of air remaining in thelungs after a maximal exhalation. VC vital capacity is the volume of airbreath out after the deepest inhalation. Vital capacity in males is 4.8liters and in women 3.8 liters. Slow vital capacity (SVC) is the maximumvolume of air that can be exhaled slowly after slow maximum inhalation.Three male patients suffering from severe lung injury or mitochondrialdamage or COPD and Hypoxemia were treated as described below for two (2)months. Prior to treatment the subjects had limited capacity to breathe,did not respond to any other treatment, were on oxygen daily, and couldnot function. After two (2) months treatment they showed markedimprovement. In fact, dramatic results were observed within two (2)weeks. These same three patients were treated in the same way fourmonths earlier using just the sodium pyruvate formulas without thecalcium, phosphate and magnesium and showed no or little improvement inlung functions, especially in total lung capacity. One of the threepatients with COPD did show an improvement in _(SaO2) levels at the endof the two months by 3%, but total lung capacity did not change. Thesecond treatment was conducted as follows:

Five (5) milliliters of five (5) millimolar sodium pyruvate with thecalcium, phosphate, magnesium solution is filter sterilized through a0.2 micron filter. The sterile pyruvate 15 solution is placed into a“Pulmo Aid” nebulizer manufactured by DeVilbiss Co., Somerset, Pa.15501-0635. The sterile pyruvate solution is nebulized by the Pulmo Aiddevice fitted with a disposable nebulizer and inhaled by the patient.The patient inhales normally from the Pulmo Aid nebulizer until all ofthe solution has been nebulized and inhaled. This inhalation steptypically takes about ten (10) to twenty 20 (20) minutes. The patientswere treated with this inhalation therapy periodically. Initially,treatments are about four (4) times a day at about six (6) hourintervals. Treatments were reduced to three (3) times a day at abouteight (8) hour intervals after 20 days of therapy. Treatments werefurther reduced to once a day 60 DAYS AFTER ONSET OF TREATMENT. Aftersixty (60) days treatments are three to five times a week. The followingdata shows results of various lung capacity and lung function testsadministered before treatment and two (2) months after treatment wascommenced.

Total vital capacity averaged in the three patients increased from 2.2liters to 3.5 liters, an increase of 33% and _(SaO2) levels increased byover 6% in all the patients. Conclusion: Treatment did the following:(1) Improved lung vital capacity by 33% (2) Decreased some medicationlevels and ceased use of oxygen. (3) COPD is reduced to the point thatroutine use of inhalers is not needed. (4) Increased lung capacity by34%.

Example VII: Clinical Trial 1

Eighteen subjects with allergic rhinitis and various other sinusdiseases, who were regular nasal spray users were given EmphyClear™, aSodium Pyruvate+Saline Nasal Spray to use at home two or three times aday for seven days, in place of their regular nasal spray. Several ofthese subjects regularly used saline, or OTC nasal products and severalused steroid-based nasal sprays. Forty percent of subjects suffered fromat least one oropharyngeal disorder; the most frequently reported werehoarseness, tingling, mouth irritation, and reddening due to the use ofinhaled steroids. Prior to, and at the end of the study period, thesubjects' nostrils were examined for mucosal fragility, lesions,erythema, and edema using a rhinoscope. These pre- and post-study nasalcharacteristics were rated on a five point zero (“none”) to four(“severe”) scale, and compared.

Conclusions:

All 18 subjects completed the study, and none opted to return to theirnormal nasal spray therapy during this period. The data obtained fromthe rhinoscopic examinations indicated that the Sodium Pyruvate+SalineNasal Spray did not induce dermal irritation and was effective insignificantly (p=0.006) reducing the erythema in subjects who normallyuse either saline or non-saline nasal sprays including steroids whenpre-test ratings were compared to post-test ratings. Further, subjectiveevaluations from the subjects indicated a positive preference for theSodium Pyruvate+Saline Nasal Spray, with 83% of all subjects sayingEmphyClear™ was “Better Than” or “Comparable To” their present therapywith regard to “Soothing;” and a like percentage of all subjects sayingEmphyClear™ was “Better Than” their present therapy for relievingsymptoms. 94% of all subjects said it was “Better Than” their presenttherapy with regard to less 30 “Stinging.” When questioned by theInvestigator, 17 of 18 subjects stated that EmphyClear™ “Opened NasalPassages,” and “Cleared Congestion, reduced snoring, moisturized theirnasal passages and enhanced their ability to sleep all night.” Theseresults were consistent whether the subject normally used a saline orsteroid-based nasal spray. This study clearly showed that delivery ofsodium pyruvate can reduce nasal congestion, swelling, inflammation andenhanced their sleeping. When several of these patients assessed thepyruvate formula with the calcium, phosphate and magnesium against thestandard sodium pyruvate solution in saline, they reported the addedbenefits of, less lung tightness, less mucus production which is due toan increase of sinus and lung surfactants and reduction of one or moreoropharyngeal disorder; hoarseness, tingling, mouth irritation, andreddening.

Example VIII: Fourteen-Day in-Use Evaluation of Nasal Sprays ContainingSodium Pyruvate and Reduced Steroids

Nasal Sprays are used by consumers to relieve congestion, nasal dryness,inflammation, itchiness, redness, and other allergy type symptoms. Formild symptoms, nasal sprays containing only saline are typically used bypeople who suffer from nasal congestion symptoms. However, individualswho have moderate to severe chronic sinus problems with associated nasalinflammation, use nasal sprays that contain steroids. Thesesteroid-containing sprays reduce inflammation and provide superiorrelief compared to saline-only products. However, chronic use of thesesteroids can cause problems in the respiratory tract and ultimately leadto 20 “rebound congestion” (Rhinitis Medicamentos). This “reboundcongestion” actually worsens the subject's nasal morphology andphysiology, leading to increased nasal congestion and inflammation. As aresult, the chronic use of steroid nasal sprays is discouraged by theproducts' manufacturers' and most physicians. Excess use of steroids hasalso been associated with hypoxemia. Nine regular Flonase® subjects andeight regular Nasacort® subjects who suffered chronically from nasaldecongestion were recruited to evaluate comparable products containing areduced level of steroids (50-70% reduction in the drug) in a 5 mMsodium pyruvate solution. Prior to beginning the study, the subjectswere asked to rate their current product on a 10 point visual analoguescale (VAS) with 0 being “terrible” and 10 being “excellent” for thefollowing categories: soothing the nostrils, relieving symptoms, stingof nostrils, and overall rating of satisfaction. The subjects on averagerated their current products “good,” with little difference between thetwo products except for a trend toward perceived better “soothing” withNasacort® than with Flonase®.

Upon beginning the trial, the subjects were blinded regarding their TestProduct, and they used the Test Product exclusively for 14 days. Thesubjects' nostrils were objectively evaluated using a nasoscope at days0, 7, and 14, and physical exams, including vital signs were alsoadministered on days 0, 7, and 14. During the 14 day 5 test period thesubjects subjectively evaluated the Test Product on a daily basis usinga 10-point VAS questionnaire. The categories included comparison of theTest Products to the subjects' normal therapy in their ability to sooththe nostrils, relieve symptoms, cause/reduce stinging, relievedecongestion, and quantify usage, and rate the product on an “overall”basis. After seven and fourteen days, nasoscope evaluations revealed atrend in reduction of aberrant morphologies for the “Reduced-StrengthFlonase®” Test Product compared to the nasoscope evaluations obtained onDay 0; and a significant reduction in aberrant morphologies for the“Reduced-Strength Nasacort®” Test Product. These objective observationsare consistent with the subjective evaluations where the subjects rated“Reduced-Strength Flonase®” Test Product as “Comparable” or “Better” inall categories, and rated “Reduced-Strength Nasacort®” Test Product as“Better” in all categories. The Test Products were subjectively judgedto be comparable or better than the Flonase® or Nasacort® that thesubjects typically used. The subjects did not rate the Test Productslower than the Flonase® or Nasacort® in any category. The Test Productswere rated as “Better” in comparison to the “Soothing,” “Stinging” and“Relief of Symptoms” characteristics of Flonase®, and, with regard toNasacort®, the 25 subjects rated the Test Product as “Comparable” acrossall categories after 14 days of use. End-of-Trial subjective commentswere also highly favorable to the Test Products compared to Flonase® andNasacort®. Additionally, when asked if they might purchase the product,the subjects' average result was 5.4±1.0, indicating that the subjects“Might Purchase,” or were “Likely to Purchase,” the Test Product.

Conclusion:

“Reduced-Strength Flonase®” and “Reduced-Strength Nasacort®” TestProduct nasal sprays were found to be as effective as the“full-strength” (i.e. commercial) Flonase® and more effective than thecommercial Nasacort® when the reduced commercial “active ingredients”were delivered to the subjects in a 5 mM (0.55 mg/mL) sodium pyruvatesaline solution. Pyruvate and steroids acted synergistically. Bythemselves, steroids can be toxic and irritating and habit forming. Whenplaced together with pyruvate, they acted synergistically to reduceinhaled steroid levels and complemented their reactions in the humanbody. The 5 mM pyruvate solution in combination with reduced steroids,balanced the negative effect of steroids and enhanced the effect ofsteroids allowing us to reduce steroids by 70% and obtain the sameeffect as the full dose of steroids. The sodium pyruvate formula withcalcium, phosphate and magnesium, worked better and expectantly lessirritating to the nasal cavities and sinuses and reduction of oneoropharyngeal disorder; hoarseness, tingling, mouth irritation, andreddening, than the sodium pyruvate in saline alone. In a similarexperiment described above, a commercial Rhinocort nasal formula (32 mgof budesonide) was diluted with 5 mM sodium pyruvate formulation todeliver 16 mg of budesonide (50% of the commercial formulation) to the 4patients that use Rhinocort and that suffered with allergic rhinitis andsinusitis, and other nasal inflammatory diseases. These patients ratedbudesonide 4 on a 1-10 irritation scale with 1 being the most irritatingand 10 being non irritating to the sinuses. These patients weresquirting each nostril 2-3 times each, two to three times daily, whichis 12-18 daily squirts, far exceeding FDA standards of 240 mg dailyusage of this steroid. When these patients tested the 50% formulationwith sodium pyruvate, they obtained the same efficacy, but with half theusage of the steroid, but still using 12-18 squirts daily. They ratedthe product a 5. When the budesonide was diluted with calcium pyruvate,the patients rated this formula a 6 and reported that they used equal ormore squirts to obtain efficacy. When these patients tested the 50%formula with the sodium pyruvate, calcium, phosphate and magnesiumformula, they rated the product a 8 and all the patients recorded a20%-30% reduction in usage, 8-12 squirts daily usage, clearly showingthat the sodium pyruvate with calcium, phosphate and magnesium wassynergistic and un expectantly less irritating to the nasal cavities andsinuses and reduction of one or more oropharyngeal disorder; hoarseness,tingling, mouth irritation, and reddening. See table V.

TABLE V Comparison of various salts of pyruvate in 5 mM salt solutionswith commercial steroids that were diluted by 50% in patients withAllergic Rhinitis at 14 days. Overall rating was 1-10 with 1 being themost negative and 10 being the best result Overall Various SaltsSoothing Relief of Stinging Relief of Comparison of Rating of pyruvateof Nostrils symptoms of Nostrils congestion amount used 1-10 SodiumNasacort 6.1 5.0 6.8 6.5 6.6 6.8 Flonase 6.0 6.1 6.2 6.8 5.9 7 Rhinocort5.8 5.8 6.0 5.7 5.4 5.6 Calcium Nasocort 6.1 5.0 5.0 6.0 5.1 5.8 Flonase5.0 5.1 5.7 5.8 5.9 6 Rhinocort 4.6 5.0 4.8 5.1 5.1 5.5 Sodium pyruvate& calcium & phosphate & magnesium Nasocort 7.0 8.1 7.9 8.6 8.9 9 Flonase7.8 8.5 8.6 8.5 8.8 8.9 Rhinocort 6.8 7.4 7.8 7.5 8.3 8.4

TABLE VI Comparison of 20 mM sodium pyruvate saline nasal spray to the20 mM sodium pyruvate formula with calcium, phosphate and magnesium inCOPD patients with Allergic Rhinitis tested over a three months period.Overall rating was 1-10 with 1 being the most negative 5 and 10 beingthe best result Rating 1-10 Percentage Rating 1-10 Relief of Percentagedecrease in decrease in Congestion coughing. decrease in us Overallshortness COPD and lung Percentage of RX Rating Formulas of breathsymptoms tightness Daily decrease medications 1-10 Sodium Pyruvate 6.018.0% 5 15% 20% 7 in physiological saline Sodium Pyruvate & 8.0 52.0% 946% 48% 9 calcium & Phosphate & magnesium physiological Saline 2.0   6%4  5% 1.0%  4

Example IX: Evaluation of the Sodium Pyruvate Formula with Calcium,Phosphate and Magnesium to the Sodium Pyruvate Solution without Calcium,Phosphate and Magnesium with Various Drugs in Patients with Injured LungMitochondria that have Hypoxemia

With the hundreds of patients tested in our various clinical trials,data was gathered as to the type of medications the patients used andthe frequency of their use over a six-month period. The patients wereasked to rate their medications form 1-10 with 1 being the mostirritating with the most side effects and 10 being the best with noirritation and no side effects. In these clinical trials, various drugswere evaluated for irritation, mucus production, and efficacy in humans.The drugs were all evaluated using their current formulations andconcentrations against the same formulations with the addition of sodiumpyruvate, with the calcium, phosphate and magnesium formula given justprior to the use of their medications. They were instructed to 20 inhalethis formula just prior to the use of their medications and to evaluatethe effect of their medications on the 1-10 scale. Scores are based onuser scoring of the product and are on a 1-10 scale with a 1 score beingvery irritating and having side effects, 5 being comparable to thecurrent product and above 5 being better than the current commercialproduct (less irritating and fewer side effects) see table VII.

We evaluated the following medication and the ones that worked with thesodium pyruvate, calcium, phosphate and magnesium formula were the nasaland lung steroids Flonase, Nasacort, Nasonex, Tobramyci anantibacterial, Aztreonam 10 lysine an antimicrobial, Zanamivir for thetreatment of influenza A and B, Pentamidine isethionate—anantimicrobial, Bactroban (Mupirocin) and antibacterial, Ribavirin (anantiviral), Vancomycin for the treatment of Staph infections, Sprix(ketorolac Tromethamine), Patanase for nasal allergies (antihistamine),nicotine, Epinephrine, Cromoglycate, Combivent, acetylcysteine andinsulin. All of the medications listed above have three or more of theside effects listed: Chest pain, nausea, vomiting, coughing,bronchospasm, headaches, hypoventilation, hypotension, bradycardia,increased infections, blurred vision, mucosal irritation, fatigue, andshortness of breath and a decrease in _(SaO2) values. In patients (36)with constant lung infections, bacterial or viral, the 20 mM sodiumpyruvate formula with calcium, phosphate and magnesium reduced theamount lung or sinus infections by 54% over the course of a year, whichis very significant.

Patients on the various inhaled medications whether inhaled or takenorally or by IV infusion, were enlisted in the evaluation of the inhaledsodium pyruvate calcium, phosphate and magnesium formula. The patientswere tested for their _(SaO2) levels and those that had _(SaO2) levelsbelow 92% were asked to enlist in the study. Nearly 50% of all patientson inhaled medications or other non-inhaled medications exhibitedHypoxemia due to their medical conditions or the medications theyreceived. After the SaO2 levels were determined prior to and one hourafter taking their medications, the patients returned the following day,_(SaO2) measurements were taken one hour prior to taking theirmedications. The patients were then handed the hypotonic inhalationformula of sodium pyruvate with calcium, phosphate magnesium formula andinstructed to inhale it one hour before taking their medications,_(SaO2) measurements were then taken one hour after taking theirmedications. See table VII.

TABLE VII Comparison of various drugs administered in patients withchronic Hypoxemia. Overall rating was 1-10 with 1 being non- effectiveand 10 being the best result for total lung function tests. Lungfunctions were measured as reduction in lung tightness and coughing,ease of breathing and decrease in hypoxemia as measured by an increasein SaO2 levels Drug in Drug in commercial Drug in commercial formulawith Pre- commercial formula with pre- inhaled sodium pyru- Drugs inDrugs in formula taken in inhaled sodium py- vate, calcium & commercialcommercial prescribed way. ruvate saline only. phosphate & mag- Drugscommercial formula with pre- formula Pre-inhaled SaO2 measurementsmeasurements taken nesium. measurements formula given as inhaled sodiumsodium pyruvate & taken after medica- after taking the taken aftertaking instructed in the pyruvate in saline calcium & phosphate tion andcompared medication and com- medication and package only & magnesium tobaseline pared to baseline compared to baseline Various Lung Lung LungSaO2 SaO2 SaO2 Drugs functions functions functions MeasurementsMeasurements measurements Pentamidine 4 5 8 −1 +1 +2 isethionateMupirocin 4 6 8 0 0 +4 Tobramycin 5 5 6 −2 0 +3 Vancomycin 6 5 8 −1 0 +1Aztreonam 8 8 7 −1 0 +4 Zanamivir 4 5 7 −2 0 +5 Ribavirin 5 6 7 −3 0 +2Albuterol 8 8 8 0 +1 +4 Patanase 7 7 8 0 0 0 Chlotrimizole 4 6 8 −2 +1+1 Epinephrine 3 4 5 +1 0 +6 Cromoglycate 3 6 7 0 0 +5 Flunisolide 6 6 6−1 +1 +4 Nicotine 3 6 8 −3 +2 +4 Insulin 5 6 7 −2 +1 +4 Butorphanol 6 79 −2 0 0 Imetrex 7 7 7 −3 0 0 Acetylcysteine 4 6 8 +1 0 +4 Flonase 4 5 90 +1 +5 Levorphanol 2 6 8 −6 +1 +6 Tartrate

As can be seen in table VII, the best formula was the sodium pyruvateformula with calcium phosphate and magnesium. The commercial drugformulas listed above by themselves averaged a 5.1. The addition ofsodium pyruvate raised that to 6.1, an increase of 17%. The addition ofthe sodium pyruvate with calcium, phosphate and magnesium raised that toan average of 7.3, a 31% reduction of side effects. The commercial drugformulas listed above by themselves averaged a zero for _(SaO2) whereasthe pretreatment with the inhalation of the sodium pyruvate, calcium,phosphate and magnesium increased saw levels by 3% a clinicallysignificant improvement. Only the patients treated with the sodiumpyruvate, calcium, phosphate and magnesium formula stated they couldbreathe better with less lung tightness.

Example X: Mucolytic

The sodium Pyruvate, calcium, phosphate and magnesium solution wasassessed with inhaled acetylcysteine which is FDA approved. Inhaledacetylcysteine is indicated for mucolytic (“mucus-dissolving”) therapyas an adjuvant in respiratory conditions with excessive and/or thickmucus production. Such conditions include emphysema, bronchitis,tuberculosis, bronchiectasis, amyloidosis, pneumonia, cystic fibrosisand (COPD) Chronic Obstructive Pulmonary Disease. It is also usedpostoperatively, as a diagnostic aid, and in tracheotomy care. It may beconsidered ineffective in cystic fibrosis. However, a recent paper inthe Proceedings of the National Academy of Sciences reports thathigh-dose oral N-acetylcysteine modulates inflammation in cysticfibrosis and has the potential to counter the intertwined redox andinflammatory imbalances in CF. Oral acetylcysteine may also be used as amucolytic in less serious cases. Inhaled acetylcysteine is indicated formucolytic (“mucus-dissolving”) therapy as an adjuvant in respiratoryconditions with excessive and/or thick mucus production. For thisindication, acetylcysteine acts to reduce mucus viscosity by splittingdisulfide bonds linking proteins present in the mucus (mucoproteins).The sodium Pyruvate, with the calcium, phosphate and magnesium formulawas added to a commercial formula of acetylcysteine and was found toenhance its mucolytic activity. When many of these patients assessed thesodium Pyruvate, calcium, phosphate and magnesium formula against thestandard sodium pyruvate solution in saline, they reported an addedbenefit less lung tightness, less mucus production which is due to anincrease of sinus and lung surfactants. The use of pyruvyl-cysteine wasas effective as acetylcysteine.

Example XI: Horse Racing

When horses race, they sometimes bleed through the nostrils and sufferfrom hypoxemia. Three horses with breathing and bleeding problems weretreated with a 20 mM nasal solution of sodium pyruvate with calcium,phosphate and magnesium (surfactant enhancer). The horses were treatedby squirting each nostril 10 times each, one hour before racing andagain just a few minutes before racing. The use of the Surfactantenhancer eliminated the bleeding and enhanced the horse's performances.They actually started winning races, whereas they would always loose.Their breathing problems disappeared.

Example XII: Treatment of Migraines

The use of the surfactant enhancer pyruvate nasal spray to relievemigraines, blurred vision and sinus congestion. The nasal spray relievedmigraines and blurred vision and congestion in all 15 patients tested.The National Headache Foundation estimates that 28 million Americanssuffer from migraines. More women than men get migraines and a quarterof all women with migraines suffer four or more attacks a month; 35%experience one to four severe attacks a month, and 40% experience one orless than one severe attack a month. Each migraine can last from fourhours to three days. People with migraines may inherit the tendency tobe affected by certain migraine triggers, such as fatigue, brightlights, weather changes, and others. There is a migraine “pain center”or generator in the brain. A migraine begins when hyperactive nervecells send out impulses to the blood vessels, causing them to clamp downor constrict, followed by dilation (expanding) and the release ofprostaglandins, serotonin, and other inflammatory substances that causethe 30 pulsation to be painful. Many migraines seem to be triggered byexternal factors. Possible triggers include: Emotional stress,Sensitivity to specific chemicals and preservatives in foods, Caffeine,Changing weather conditions, Menstrual periods, Excessive fatigue,Skipping meals, and Changes in normal sleep pattern. It became obviousfrom the results of the clinical trials, that the sodium pyruvate withcalcium, phosphate and magnesium formula nasal spray relieved migrainesand reduced swelling and congestion and the pain associated withmigraines.

Example XIII: Sleep Aids

We tested a nasal formulation with sleep aids. All the patients thatused our 20 mM sodium pyruvate with calcium, phosphate and magnesiumformula nasal spray stated they slept better. We then took this nasalspray and added tryptophan a known sleep agent found in turkey meat. Theaddition of tryptophan worked synergistically to enhance sleep inpatients that used it. Inhalation products for sleeping disorders werecombined with the sodium pyruvate with the calcium, phosphate andmagnesium formula. They included, migranal (dihydroergotamine mesylate)stadol, (butorphanol) Imetrex, for anti-snoring. Two children withAutism, reported that the use of the 20 mM sodium pyruvate with thecalcium, phosphate and magnesium formula nasal spray calmed them downand allowed them to sleep all night.

Example XIV: Sleep Apnea

Sleep Apnea is a sleep disorder characterized by pauses in breathing orinstances of shallow or infrequent breathing during sleep, with areduction in _(SaO2) values caused by reduced levels of synthesizedphospholipids. Each pause in breathing, called an apnea, can last forseveral seconds to several minutes, and may occur, by definition, atleast 5 times in an hour. Similarly, each abnormally shallow breathingevent is called a hypopnea. When breathing is paused, carbon dioxidebuilds up in the bloodstream. Chemoreceptor's in the blood stream notethe high carbon dioxide levels. The brain is signaled to wake the personsleeping and breathe in air. Breathing normally will restore oxygenlevels and the person will fall asleep again. There are three forms ofsleep apnea: central (CSA), obstructive (OSA), and complex or mixedsleep apnea (i.e., a combination of central and obstructive)constituting 0.4%, 84%, and 15% of cases, respectively. In CSA,breathing is interrupted by a lack of respiratory effort; in OSA,breathing is interrupted by a physical block to airflow despiterespiratory effort, and snoring is common. According to the NationalInstitutes of Health, 12 million Americans have OSA. There are morecases of sleep apnea still because people either do not report thecondition or do not know they have sleep apnea. In other words, commoneffects of sleep apnea include daytime fatigue, a slower reaction time,and vision problems. OSA may increase risk for driving accidents andwork-related accidents. If OSA is not treated, one has an increased riskof other health problems such as diabetes. Even death could occur fromuntreated OSA due to lack of oxygen to the body. There is also evidencethat the risk of diabetes among those with moderate or severe sleepapnea is higher. There is also increasing evidence that sleep apnea mayalso lead to liver function impairment, particularly fatty liverdiseases. People who smoke have sleep apnea at three times the rate ofpeople who have never smoked. Mild occasional sleep apnea, such as manypeople experience during an upper respiratory infection, may not beimportant, but chronic severe obstructive sleep apnea requires treatmentto prevent low blood oxygen (hypoxemia), sleep deprivation, and othercomplications. Snoring is a common finding in people with this syndrome.Snoring is the turbulent sound of air moving through the back of themouth, nose, and throat.

The sodium Pyruvate formula with calcium, phosphate and magnesiumincreased lung and sinus surfactants to decreases congestion andinflammation and increases oxygen saturation to help patients with SleepApnea. In all of the clinical studies, approximately 20% of the patientstreated with our nasal spray or inhalation therapy (460 patients),reported that they suffered from Sleep Apnea, and that the use of ourinhaled surfactant enhancer allowed them to sleep all night withoutsnoring or waking up.

Example XV: Smokers, how Nicotine Inhalation in the Sinuses or LungsIncreases Hypoxemia

The primary therapeutic use of nicotine is in treating nicotinedependence in order to eliminate smoking with its health risks. Nicotinecan also be irritating and has the ability to lower _(SaO2) values wheninhaled in smoke while increasing hypoxemia. We placed nicotine into amodified formula sodium pyruvate and calcium, phosphate and magnesiumand discovered that inhaled nicotine (nasal or lungs) was well toleratedover nicotine by itself, which was irritating. The combination wassynergistic. Smokers who used this formula rated the sodium pyruvate,calcium, phosphate and magnesium nicotine formula much higher thannicotine by itself. They reported that nicotine delivered this way wasfaster than the patch and much less irritating. The patient squirtedeach nostril three times which is equivalent to 0.66 mg of pyruvate perdose per nostril which is 1.32 mg of pyruvate being delivered per dosetimes 2 times per day is 2.64 mg of pyruvate delivered per daily dose.Approximately 0.020 mg to 0.03 mg of nicotine was delivered. Nicotinedelivered only with sodium pyruvate in saline solution, was a littlemore irritating and the ability of each patient to determine the effectof nicotine was delayed by 26%. _(Sa02) levels in these patients rose by4% with the sodium pyruvate, calcium, phosphate magnesium formula.

Example XVI: Cancer Drugs Often Cause Lung Cell Damage and Inhibit theSynthesis of Membrane Phospholipids to Cause Lung Tightness, Coughingand Hypoxemia

This treatment might offer promise in battling lung cancer, the leadingcause of cancer-related deaths in the United States, and the second-mostcommon cancer overall, according to the National Cancer Institute (NCI).About 160,000 Americans died from the disease last year, which costs theU.S. nearly $10 billion in medical bills, according to the NCI. Somechemotherapy drugs can affect the lungs (pulmonary toxicity). The exacteffect of chemotherapy drugs that cause lung problems is not fullyknown. It may be that the drugs cause inflammation in the lung cellsthat result in a lung infection (pneumonitis). The drugs may also causefibrous, scar-like tissue to form in the lungs (pulmonary fibrosis) andrestrict lung function. Lung damage is often related to the dose of thedrugs used. Chemotherapy drugs that are known to cause lung damage are:Bleomycin (Blenoxane)—most common. Lung damage occurs in up to 10% ofpeople who receive this drug. The risk increases when higher doses areused. With Carmustine (BiCNU, BCNU) lung damage occurs in about 20%-30%of people who receive high-dose therapy with this drug. Methotrexatepulmonary toxicity occurs in up to 8% of people who receive this drug.With Alkylating drugs, such as cyclophosphamide (Cytoxan, Procytox) orbusulfan (Busulfex) lung damage occurs in less than 1% of people whoreceive these drugs. Lung damage occurs more often in people who: areelderly People over 70 years of age, have a higher risk of developinglung problems, have a personal history of lung disease, like COPD, orhave received radiation therapy to the lungs. Symptoms of lung damageinclude: dry cough, shortness of breath (especially with activity) lungtightness, and fatigue. Symptoms can occur during treatment withchemotherapy or a few months after treatment ends. Damage to the lungtissue is usually not reversible.

Changes to lung tissue may be detected with: blood tests to check thelevel of oxygen in the blood, such as blood gas analysis or oxygensaturation tests that measure lung function, such as pulmonary functiontest (PFT). When shortness of breath occurs, it may be treated with:oxygen therapy and drugs to reduce inflammation, bronchodilator drugs towiden the bronchi (large tubes, or airways, in 15 the lungs).

Hypoxia within regions of solid tumors including lung cancers, isassociated with resistance to standard treatments, particularlyradiotherapy. Conventional drug therapy, which depends on reaching thecancer through the bloodstream, can be less effective in hypoxic tumors.Low oxygen levels in a cell interrupt the activity of oxidativephosphorylation, a term for the highly efficient way that cells normallyuse to convert food to energy. As oxygen decreases, the cells switch toglycolysis to produce their energy units, called ATP. Glycolysis is adrastically less efficient way to obtain energy, and so the cancer cellsmust work even harder to obtain even more food, specifically glucose, tosurvive. When oxygen levels dip dangerously low, angiogenesis, or theprocess of creating new blood vessels, begins. The new blood vesselsprovide fresh oxygen, thus improving oxygen levels in the cell and tumorand slowing the cancer growth—but only temporarily.

Drug designers have taken advantage of the hypoxic regions in tumors anddesigned anticancer drugs that are specifically active or activatedunder hypoxic conditions. For example, hypoxia-activated prodrugs like3-bromopyruvate, are chemically modified to be inactive, but whenadministered to the body and exposed to hypoxic conditions (such as in atumor), they are metabolized or otherwise converted into the active,anticancer form. Despite these new drugs, there is an ongoing need forinnovative approaches to anticancer therapy. This patent highlightsvarious treatment options available for increasing lung surfactants thatare responsible for increasing blood oxygen levels in cancer Patientsthus targeting hypoxic cells within tumors that could be highlybeneficial in the treatment of SCLC.

Example XVII: Pretreatment of Normal Cells Co Cultured with CancerCells, Followed by Treatment with Doxorubicin

Peripheral blood monocytes and U937 monocytic leukemia tumor cells wereplaced in sterile culture flasks and maintained in culture usingDulbecco's Minimal Essential Medium, with 10% fetal calf serum,supplemented with 2 mM glutamine and Pen/Strep. The cytotoxicity of thecytotoxic agent on the cells was analyzed by propidium iodide exclusiontechniques and flow cytometric quantitation. Viability of the cells wasquantified as the number of cells that excluded the vital dye trypanblue. Sodium pyruvate was dissolved in distilled water and the solutionwas adjusted to pH 7.4 with calcium, phosphate and magnesium. Solutionswere sterile filtered. Stock solutions were prepared so that the vehiclewould not be more than 1% of the total volume of the culture media.H-Thymidine Radiosotopic Incorporation Measurement of Cytotoxity. Themembrane surfactant enhancers agents (sodium pyruvate and calcium,phosphate and magnesium), was examined for their ability to decrease theCytotoxity of Doxorubicin to U937 monocytic leukemia cells and normalperipheral blood monocytes. The optimal concentrations of the agentsthat were able to protect cells against Doxorubicin induced Cytotoxitywere the 5 mM of sodium pyruvate, calcium, phosphate and magnesiumformula. Susceptibility studies were conducted to determine the optimaltreatment time of the cells with the cryoprotective agents prior totreatment of the cells with the cytotoxic agent. The normal cells andU937 leukemic tumor cells were pretreated separately in “wash out”studies with the single agents alone, and in combination, at the optimalconcentration described above for various time periods, washed withfresh medium to remove the agents, and treated with the cytotoxic agent.The co-culture of normal and U937 leukemic minor cells was treatedessentially in the same manner except that the cells were not treatedseparately, but co-cultured. The optimal pretreatment time of the cellswith the membrane enhancer agents was found to be 24 hours prior totreatment of the cells with Doxorubicin. The cells were then placed inculture medium without the protective agents. The length of time thatthe cytoprotection lasted was 24 hours following Doxorubicin treatment.At this time, peripheral cell viability is a limiting factor becausethese cells are normal cells and do not remain in culture for extendedperiods of time. Normal and U937 tumor cells were co-cultured and theCytotoxity of Doxorubicin on the cells was determined by viabilityassays which examined the differential ability of the cytoprotectivecompositions alone, and in combinations, to protect the normal cellsfrom the Cytotoxity of the chemotherapeutic agent. The cells wereisolated and examined for morphological evidence of cytotoxicity orprevention of cytotoxicity. These studies determined the cytoprotectiveeffect of the surfactant enhancer on the normal and tumor cells. DNAsynthesis studies using 3Hthymidine (1 uCi/well) were carried out 4hours prior to termination of the experiment to determine the effect ofthe formulations on the proliferation of the cells as a measure of theprevention of cytotoxicity and the extent of Doxorubicin-inducedcytotoxicity. Propidium iodide exclusion analysis was carried out fordirect quantitation of the cytotoxicity and the prevention ofcytotoxicity. Each set of studies was performed in triplicate so thatstatistical analysis of the significant differences between thetreatment groups could be conducted. The surfactant enhancer combinationof 5 mM sodium pyruvate and calcium, phosphate, and magnesium formula,provided significant protection to the normal peripheral monocytes anddid not protect the tumor cells from the effects of the Cytotoxic agent.Wash-out studies were conducted to determine viability of the peripheralblood monocytes co-cultured with U937 monocytic leukemia cells after 24hour pretreatment of the cells with the surfactant enhancer, which isalso a mitochondrial protective agent, followed by administration ofDoxorubicin. The viability of the control normal peripheral cells wasenhanced from 55% to 68% with the use of 5 mM sodium pyruvate andcalcium, phosphate and magnesium formula, whereas the viability of thecontrol U937 cells was decreased from 43% to 12%. Thus, the use of thesurfactant synthesis enhancer protected normal cells for 24 hours, whilethe leukemia cells died. See table VIII.

TABLE VIII Comparison of various cancer drugs in various media.Percentage of viable non-cancerous cells after incubation withanticancer drugs Drugs in Drugs in Drugs in commercial commercialcommercial formula with Percentage of Drugs in formula with formula withsodium pyruvate viable commercial sodium pyruvate sodium pyruvate withcalcium & cells after formula with without calcium & with calcium &phosphate & incubation sodium phosphate & phosphate & Magnesium VariousDrugs with drugs chloride only magnesium magnesium repeat studyanastrozole 24 25 50 86 94 Bleomycin 31 33 47 98 98 cisplatin 46 43 5888 91 Carboplatin 42 50 56 87 97 floxuridine 38 38 58 92 91 methotrexate42 43 68 94 98 oxaliplatin 23 24 41 95 98 Bevacizumab 21 27 40 88 87

Other drugs tested produced similar results, shown in the above table,including Crizotinib, Docetaxel, Erlotinib, Etoposide, Gemcitabine,Irinotecan, Paclitaxel, Pemetrexed Vinorelbine.

Example XVIII: Treatment of Patients with Various Cancers and LungCancer

To date most patients with cancer that are treated with radiation orcancer drugs show a partial reduction of tumor sizes, but in most casesthe cancer remains and life expectances increases for a short period oftime. This is the case for lung cancer. Five patients with variouscancers including including lung cancers, were treated with3-Bromopyruvate, an alkylating agent and a well-known inhibitor ofenergy metabolism. Results to date have been mixed. The problem withmost cancer drugs is not only their toxicity to noncancerous tissue, butis their inability to completely eradicate the cancer. Cancer drugscause hypoxia in normal noncancerous cells and they destroy lung tissueand their ability to synthesize lung surfactants, thus cause damage tosurrounding tissue. In mice studies conducted by others, theyinvestigated the chemo preventive activity of 3-bromopyruvate. For theaerosol treatment the mice were treated with 10-30 mg/5 ml daily andtreated for 8 weeks. Aerosolized 3-bromopyruvate significantly decreasedtumor multiplicity and tumor load by 40% and 60%, respectively, at adose of 10 mg/5 mL by inhalation. Interestingly, the efficacy ofaerosolized 3-bromopyruvate did not accompany any liver toxicityindicating that it is a safer safer route of administering thiscompound. Treatment with 3-bromopyruvate in tissue cultures of lungcancer cells showed an increased immune histo chemical staining forcleaved caspase-3, suggesting that the lung tumor inhibitory effects of3-bromopyruvate were through induction of apoptosis.

3-Bromopyruvate also dissociated hexokinase II from mitochondria,reduced hexokinase activity, and blocked energy metabolism in cancercells, finally triggered cancer cell death and induced apoptosis throughcaspase-3, and PARP in human lung cancer cell line. The problem with3-bromopyruvate was its toxicity to normal lung cells. The formulaneeded to protect noncancerous cells from 3-bromopyruvate and to enhanceits effect on tumors, was the addition of inhaled 20 mM solution ofsodium pyruvate, calcium, phosphate, magnesium formula inhaled 1-2 hoursprior to the inhalation of the 10 mg of 3-bromopyruvate. Theinvestigators were given the sodium pyruvate with calcium, phosphate andmagnesium formula and instructed to have the rats inhale the formula 1-2hours prior the inhalation of the cancer drug. 25 This approach reducedtumor sizes by 90% compared the 60% reduction with 3bromopyruvate byitself. The addition of dichloroacetate with 3-bromopyruvate to thesodium pyruvate with calcium, phosphate and magnesium formula was thebest formula decreasing tumor loads by 95%, especially with the additionof magnesium bicarbonate that increased the PH to 7.9 to neutralize thelactic acid produced in tumors that enhance tumorigenesis. Similareffects were seen with the inhalation of the sodium pyruvate, calcium,phosphate, and magnesium formula followed in two hours by oral orinhalation administration of the 3-bromopyruvate or doxorubicin.

Example XIX: Tumor Volume Decrease at 8 Weeks is Associated with LongerSurvival in EGFR-Mutant Advanced Non-Small-Cell Lung Cancer PatientsTreated with EGFR TKI

Departments of *Imaging, ^(†)Biostatistics and Computational Biology,Dana-Farber Cancer Institute, Boston, Mass.; ^(‡)Department of MedicalOncology and Medicine, Dana-Farber Cancer Institute and Brigham andWomen's Hospital, Boston Mass.; and Department of Radiology, Brigham andWomen's Hospital, Boston Mass. Background: The study investigatedwhether tumor volume changes at 8 weeks of therapy is associated withoutcomes in advanced non-small-cell lung cancer (NSCLC) patientsharboring sensitizing epidermal growth factor receptor (EGFR) mutationstreated with EGFR tyrosine kinase inhibitors (TKIs). Methods: In 56advanced NSCLC patients with sensitizing EGFR mutations treated withfirst-line erlotinib or gefitinib, tumor volumes of dominant lunglesions were measured on baseline and follow-up computed tomography, andwere analyzed for association with survival. Results: Among 56 eligiblepatients, the median tumor volume was 17.8 cm³ (range, 1.3-172.7 cm³) onthe baseline scans. Forty-nine patients had follow-up computedtomography at approximately 8 weeks; the median tumor volume at 8 weekswas 7.1 cm³ (range, 0.4-62.3 cm³), with the median proportional volumechange of −59% (range, −90% to +91%) from baseline. The proportionalvolume change at 8 weeks was associated with survival (p=0.02). Usingthe cutoff value of 38% volume decrease (75th percentile) at 8 weeks,patients with volume decrease more than 38% (n=37) had a median overallsurvival of 43.5 months compared with 16.3 months among those withvolume decrease of 38% or less (n=12; p 0.01). The medianprogression-free survival for patients with more than 38% volumedecrease was 12.6 months, compared with 5.5 months for those with 38% orlesser volume decrease (p=0.2). The 12 patients with 8-week volumedecrease of 38% or lesser had significantly shorter survival. Thepresent study demonstrated that proportional tumor volume decrease at 8weeks of therapy was associated with prolonged survival in advancedNSCLC patients, with sensitizing EGFR mutation treated with first-linegefitinib or erlotinib.

Example XX: Cancer Trial Pilot Study

In eleven patients with various cancers and chronic Hypoxemia, five withlung cancer, including three with non small cell lung cancer and sixwith various other cancers, were given the formula containing the sodiumpyruvate with calcium, phosphate and magnesium by inhalation, whichincreased _(SaO2) levels in these patients to enhance the effect of thechemotherapy or radiation, and increased the synthesis of lungsurfactants in lung alveoli cells to protect normal cells and helpreduce hypoxia in cancer cells. These patients inhaled the formula oneto two hours before they were treated with cancer drugs or radiation,given by current standard methods, and continued to inhale thesurfactant enhancer formula twice a day for the eight weeks followingthe chemo therapy treatment. Because these patients are older, theyoften lack good nutritional eating habits, which effects their immunesystem. Thus, the patients were also given a proprietary diet high in aunique blend of antioxidants, and nutrients, that they consumed everyday before and after chemo or radiation. Good nutrition is always a pluswhen patients undergo chemo or radiation as sited in numerous publishedarticles. The diet specifically designed for patients with cancer andhypoxemia included calcium pyruvate, dicalcium phosphate and magnesiumin their components. The diet included Lecithin which containsPhosphatidylcholine one table spoon daily needed for phospholipidsynthesis in cells and mitochondria and to protect them from chemo,calcium pyruvate 6 grams daily, Magnesium pyruvate 1 gram with 350 mg ofmagnesium needed by mitochondrial enzymes, calcium phosphate ordicalcium phosphate 1 gram needed by cellular enzymes to maintainhemostasis, Baker's yeast one oz. scoop daily to provide other precancer nutrients and vitamin E 400 units or more.

In patients with severe Hypoxemia, Oxygen therapy was continued and thepatient also inhaled the surfactant enhancer formula prior to and afterchemotherapy for eight weeks. These patients continued chemo therapybeyond the eight weeks and ten patients are still alive six to 10 yearslater, beating the national survival rate by 4 years. Other drugs testedgiven by IV or oral standard treatments reduces tumor sizes or loads byan average 29.2% as sited in the literature. These drugs wereCrizotinib, Docetaxel, Erlotinib, Etoposide, Gemcitabine, Irinotecan,Paclitaxel, Pemetrexed, Vinorelbine. The inhalation of the surfactantenhancer decreased tumor loads and sizes, that was averaged among theeleven patients was 54.5%, a statistically and clinically significantresult. This clearly showed that decreasing hypoxemia and increasingoxygen levels at hypoxia tumor sites increased the efficacy ofchemotherapy or radiation and enhanced the reduction of tumor loads andsizes which increases survival rates significantly. One patient withlung cancer and pulmonary hypertension and COPD was treated with variouscancer drugs including Gefitinib, erlotinib or doxorubicin over a yearperiod. His lung cancer did not respond well to any of the treatmentsand his tumors shrank by only 15%. Pulmonary arterial hypertensioncauses the arteries that carry blood from the heart to the lungs tonarrow, resulting in decreased oxygen flow to the blood vessels. Whenthe body is deprived of vital oxygen, the blood pressure in thepulmonary arteries spikes above the normal range compressing the heart'sright ventricle. The pressure on this area will eventually cause theright side of the heart to swell, gradually weaken, and restrict bloodflow to the lungs. If left untreated, pulmonary hypertension can end inheart failure. The current treatment is the inhalation of Nitric oxidegas. As stated in table III the addition of the N-acetylcysteine to thephospholipid membrane enhancer formula increased Nitric oxidedramatically over any other pyruvate salt formulas. We had the patentpre and post inhale the sodium pyruvate with calcium, phosphate andmagnesium formula with the addition of the N-acetylcysteine during thenext round of chemotherapy. His _(SaO2) levels rose by 5% and his nitricoxide levels increased by over 225% compared to the standard sodiumpyruvate formula in saline, without the addition of calcium, phosphateand magnesium, that raises nitric oxide by 19% an 11 times greaterincrease. His tumor load and size shrank by 78% in eight weeks and inhis next round of treatment the tumors disappeared. His pulmonaryhypertension also disappeared. He is still alive four years later,beating the odds-on survival. Aeroshot Inc sells a caffeine inhaledproduct that delivers 100 mg of caffeine. One of the patients with lungcancer that was treated with cisplatin used the Aeroshot product alongwith the surfactant enhancer and decreased tumor sizes by 60% in eightweeks. Caffeine is thought to increase the antitumor effect of cisplatinor DNA-damaging agents because it is known that caffeine inhibits DNArepair. It appears from the results in this patient that the addition ofcaffeine to the surfactant enhancer (sodium pyruvate with calcium,phosphate and magnesium) enhanced the effect of the cisplatin.

Example XXI: Immunotherapy's Especially for Non-Small Cell Lung Cancer

Keytruda (pembrolizumab), Yervoy (ipilimumab), Opdivo (nivolumab),Tecentriq (atezolizumab) are medicines that may treat your lung cancerby working with your immune system. They can cause your immune system toattack normal organs and tissues in many areas of your body and canaffect the way they work. These problems can sometimes become serious orlife-threatening and can lead to death. These problems may happenanytime during treatment or even after your treatment has ended. Seriousside effects may include lung problems (pneumonitis). Symptoms ofpneumonitis may include: new or worsening cough; chest pain; andshortness of breath. In all these cases these drugs increase hypoxemiaby inhibiting the synthesis of lung surfactants. Several patients thatreported lung problems with the use of these medications (new orworsening cough; chest pain; and shortness of breath) were given ourinhaled formula containing the sodium pyruvate, with calcium, phosphateand magnesium. They reported that their lung problems were eliminated,after using the inhaled formula.

Example XXII: Four-Week Use of Oxymetazoline Nasal Spray Once Daily atNight Induces Rebound Swelling and Nasal Hyperreactivity that can beReversed with the Addition of the Sodium Pyruvate, Dicalcium PhosphateMagnesium Formula. Ohio State University Medical Center 2001

A randomized double-blind parallel study with 90 healthy volunteers wasperformed to examine the effect of oxymetazoline nasal spray on thedevelopment of rhinitis medicamentosa. For 30 days, 45 subjects weregiven oxymetazoline nasal spray once daily at night and placebo in themorning and at noon, The other 45 patients were given oxymetazolinenasal spray with 20 mM sodium pyruvate with calcium, phosphate andmagnesium by inhalation, which increased _(SaO2) levels in thesepatients once daily at night and placebo in the morning and at noon,before and after the course of treatment, the mucosal surface positionswere determined with rhinostereometry, followed by histamine challengetests. In the morning and the evening just before use of the nasalspray, symptoms of nasal stuffiness were evaluated on visual analoguescales (0-100). After 30 days, rebound swelling and nasal stuffinessoccurred only in the oxymetazoline group without the addition of thepyruvate formula. In the group receiving oxymetazoline nasal spray oncedaily at night, the mean rebound swelling was 1.1 mm (p<0.01) and theestimated mean symptom score for nasal stuffiness in the evening was 43(p<0.05). In the group receiving oxymetazoline with the pyruvateformula, nasal spray once daily at night, the mean rebound swelling was0.1 mm (p<0.01) and the estimated mean symptom score for nasalstuffiness in the evening was 3 (p<0.05). The finding of an increase inhistamine sensitivity in the oxymetazoline without the pyruvate formula,was taken to indicate nasal hyperreactivity. It is concluded that therisk of developing rebound swelling and nasal hyperreactivity remains,with oxymetazoline nasal spray when used once a day for 30 days, but notwhen Oxymetazoline contained the sodium pyruvate formula with calcium,phosphate and magnesium.

Example XXIII: Concussions

The secondary effects of cranial trauma that may further compromisebrain function are edema, hypoxia, hemorrhage, infection and oxygenradicals. Other important components of posttraumatic cerebralpathophysiology include, but are not limited to, generation of lacticacid, decreased intracellular magnesium, free radical production,inflammatory responses, and altered neurotransmission. Concussions alsocause impaired mitochondrial oxidative metabolism that worsens theenergy crisis in the brain. Edema may be the result of diffuse shearingof capillary, glial, and neuronal membranes or may be secondary to localcontusion or laceration. Edema can generate local pressure that cancompromise both arterial and venous cerebral blood flow, causingischemia and more edema. This may precipitate a vicious cycle sometimesimpossible to reverse. The mass effect of edema, focal or diffuse, cancause rostro caudal brain stem deterioration (possibly with herniation),a major cause of delayed death from head trauma. Brain dysfunction anddestruction are aggravated by hypoxia, the result of compromisedrespiratory function caused by the following: (1) injury to the chest,(2) aspiration pneumonia in the unconscious patient, (3) respiratorycenter depression from rostro caudal deterioration or direct damage tothe medulla, (4) pulmonary edema secondary to hypothalamic-septaldamage, or (5) status epilepticus. Blood loss from multiple injuriesand, as mentioned, brain edema further compromise delivery of oxygen tothe brain. We gave several football players the 20 mM sodium pyruvatewith calcium, phosphate and magnesium by inhalation, which increased_(SaO2) levels in these patients, to reduce brain damage and hypoxia.Measurement of reaction times can be measured by the speed of the mouseclicks to common questions. Someone with a concussion will react slowlyto these questions. The inhalation of the 20 mM sodium pyruvate withcalcium, phosphate and magnesium formula, increased reaction times by42% over the baseline measurements. In the treatments of patients withconcussions or Alzheimer's, the inhalation formulas were delivered byinhalation using a breathing mask.

Smoke Inhalation Damage and Treatment.

The same approach can be applied to smoke inhalation damage. The resultsindicate that the current pathophysiologic concept is of a diseaseprocess that leads to immediate and delayed pulmonary injury. The lunginjury process is activated by toxins in the smoke's gas and particlecomponent and by a resulting in lung inflammation. This inflammatoryprocess becomes self-perpetuating through the activation of a largenumber of inflammatory cytokines and oxygen radicals, which reduce theability of the lungs to synthesize phospholipids. Several patients withsmoke inhalation damage used the mask and testing showed an increase in_(SaO2) after the inhalation of the sodium pyruvate, calcium, phosphateand magnesium formula and reduced coughing.

TABLE IX Comparison of various salts of pyruvate against a 20 mM sodiumpyruvate nasal sprays in patients with sinus & lung diseases includingIPF and COPD. Overall rating was 1-10 with 1 being the most negative and10 being having the best rating. All nasal sprays contained 0.22% ofeach salt of pyruvate per liter of 0.9% sodium chloride. When thevarious salts of pyruvate were mixed the percentages always equaled0.22% or as an example 0.11% of sodium pyruvate and 0.11% of calciumpyruvate to equal a 20 mM solution or 0.22%. Relief of Percentagecongestion, Percentage increase of coughing Increase in Overall VariousSalts of Increased Nitric Oxide and lung SaO2 over Rating pyruvate insaline in FEV-1% over baseline Irritation tightness baseline 1-10 Sodium12.0 19.0 none 6 2 7 Calcium 7.0 17.0 None 5 1 7 Potassium 6.1 10.0 None5 no 6 Magnesium 4.0 5.1 slight 6 no 4 Zinc 1.0 2.0 Yes 4 No 3 Manganese0.0 2.0 Yes 4 No 3 Lithium 0.0 00.0 Yes 2 No 2 Aluminum 0.0 00.0 Yes 1No 1 Ammonium 0.0 00.0 Yes 1 No 1 Potassium Phosphate 0.0 0 Slight 4 No3 sodium & calcium 12.0 16 None 5 2 7 pyruvates sodium & magnesium 8.415 None 6 No 6 pyruvates sodium & calcium & 8.0 19 None 5 2 6 magnesiumpyruvates sodium & calcium & 7.0 18 None 5 2 7 pyruvate &potassiumphosphate sodium & magnesium 8.0 20 None 4 2 6 pyruvates & potassiumphosphate Sodium & calcium & 10.0 19 None 7 2%  7 Magnesium pyruvates&Potassium phosphate Sodium pyruvate 25 57.0 0 9 6%  10 & calciumchloride & magnesium chloride and potassium phosphate

Katz and Martin (current inventor) suggested the use of other salts ofpyruvate to inhale and treat nasal and lung diseases. They never testedthe individual salts for their ability to reduce inflammation orincrease lung functions. This table demonstrated that not all salts ofpyruvate produced clinically significant results and that many wereirritating. The salts of pyruvate, Zinc, manganese, lithium, magnesium,ammonium and aluminum were irritating and were much higher than bloodlevels and produced a metal taste. The combination of sodium, calciumand magnesium pyruvates with potassium phosphate did not product theclinically significant results achieved with the formula that contained0.22% Sodium pyruvate 0.90% sodium chloride, 0.01% Calcium chloride,0.01% magnesium chloride and 0.001% potassium phosphate by weight perliter of water.

TABLE X Comparison of various nasal sprays of a 20 mM sodium pyruvatesolution in patients with sinus & lung diseases including IPF and COPD.Overall rating was 1-10 with 1 being the most negative and 10 being thebest result. Percentages of ingredients in one liter of water 0.22%sodium pyruvate, 0.90% sodium chloride, 0.01% Calcium chloride, 0.01%magnesium chloride and 0.001% potassium phosphate by weight addedindividually or in combination as listed below. Formula for the sodiumpyruvate with the membrane enhancer: to one liter of purified water add2.2 gm of sodium pyruvate, 9.0 gm of sodium chloride, 0.1 gm of calciumchloride, 0.1 gm of magnesium chloride, and 0.01 gram of potassiumphosphate. Sodium pyruvate in saline with various ions of Relief ofcalcium chloride, Percentage congestion, Percentage magnesium increaseof coughing and Increase in chloride and Increased Nitric Oxide lungSaO2 over Overall Potassium phosphate in FEV-1% over baseline Irritationtightness baseline Rating 1-10 Sodium pyruvate 12.0 20.0 None 6 2 7 insaline Calcium chloride 12.0 19.0 none 5 2 7 Magnesium chloride 12.019.0 None 5 1 7 K phosphate 10.1 10.0 None 5 no 6 Calcium chloride& 11.05.1 None 6 no 5 Magnesium chloride Calcium chloride& 10.0 8.0 Yes 4 1 6Potassium phosphate Magnesium chloride & 11.4 16 None 5 2 7 potassiumphosphate Sodium pyruvate 28 57.0 none 9 6% 10 & calcium chloride &magnesium chloride and potassium phosphate Gennero culture 00 −10.0 veryIncreased −2%  1 medium 20090181007 coughing and congestion

Table X demonstrated unexpected synergistic combination of 0.22% Sodiumpyruvate 0.9% sodium chloride, 0.01% Calcium chloride, 0.01% magnesiumchloride and 0.001% potassium phosphate by weight per liter of water.Each individual component did not produce higher clinical results. Theculture medium of Gennero listed above, patent application 20090181007produces very bad results compared to the other formulas. This patentcombined dozens of ingredients, including the use of enzyme, growthfactors, sugars, nucleotide and vitamins, amino acids and sodiumpyruvate, other nutrients and calcium chloride, magnesium chloride andcalcium phosphate other ingredients to stimulate the growth of cartilageand collagen for knees and joints. When inhaled it performed very poorlyeven though it contained the ingredients in the surfactant enhancer thesodium pyruvate, calcium chloride, magnesium chloride and calciumphosphate. The other ingredients produced irritation. Mucus increased asdid coughing and did not increase lung functions. The Gennero formulaalso decreased the synthesis of nitric oxide which is critical toincreasing lung functions, and bronchodilation and reducing nasal andlung infections. The concentrations of the ingredients in the 0.22%sodium pyruvate with 0.9% sodium chloride, with 0.01% calcium chloride,0.01% magnesium chloride and 0.001% potassium phosphate by weight perliter of water was determined form blood levels of these ingredientsthat are known to work and not induce toxicity if higher levels wereused. It produced the most clinically significant results in allcategories.

Example XXIV: Inhibiting Lung Fibrosis and Increasing the Lung Functionsof FEV-1, FVC, PEF, SaO2, Nitric Oxide and (% FEV1/FVC Ratios). An OpenLabel Placebo Controlled Comparison of a 20 mM Sodium Pyruvate NasalSpray with the Surfactant Enhancer Ingredients in Patients withPulmonary Fibrosis, COPD, Diabetics, and Hypertension

There have been over 56,381 patient complaints to the FDA from patientswith Idiopathic Pulmonary Fibrosis (IPF) without COPD, and PulmonaryFibrosis with COPD, Diabetics, and patients with hypertension, statingthat Rx, OTC, and steroid-based inhalation products, have failed toprovide relief from nasal or lung inflammation nor have the ability toincrease lung functions, FEV-1, FVC, PEF, SaO2, especially FEV-1/FVCratios. This study was designed to determine the effect of inhaled 20 mMsodium pyruvate saline nasal spray with the addition of calciumchloride, magnesium chloride and potassium phosphate (surfactantenhancer ingredients) to determine if this formula would have a positiveeffect in these patients, while on or off their medications and todetermine if the nasal inhalation solutions would have any added benefitto current therapies on nasal inflammation; lung functions, includingFVC, FEV₁, PEF; and FEV-1/FVC ratios; SaO₂; expired NO, and frequency ofcoughing. Nasal steroids and other OTC nasal treatments shut down thesynthesis of nasal nitric oxide, which then leads to a decrease in lungfunctions and a 34% increase in infections, mouth breathing andcoughing.

The FEV1/FVC ratio, also called Tiffeneau-Pinelli index, is a calculatedratio used in the diagnosis of obstructive and restrictive lung disease.It represents the proportion of a person's vital capacity that they areable to expire in the first second of forced expiration (FEV1) to thefull, forced vital capacity (FVC). The result of this ratio is expressedas % FEV1/FVC ratio. Normal values are approximately 75%. In restrictivelung disease, the FEV1 and FVC are equally reduced due to fibrosis orother lung pathology like pulmonary fibrosis, which occurs in pulmonaryfibrosis, and in patients with diabetes, and hypertension.

Methods:

An initial twenty-one-day sub-chronic clinical trial was conducted thatincluded patients with Pulmonary Fibrosis with COPD and with IdiopathicPulmonary Fibrosis without COPD, that remained on their normalmedications (steroids), but were also administered the 20 mM sodiumpyruvate saline nasal spray with the surfactant enhancer ingredients(0.22% Sodium pyruvate 0.90% sodium chloride, 0.01% Calcium chloride,0.01% magnesium chloride and 0.001% potassium phosphate by weight perliter of water). If the patients were also on nasal sprays as part oftheir normal therapy, that nasal spray was eliminated. In all patientsthe test results were compared to their previous three-week screeningand baseline data (there current therapies) as the placebo control foreach variable including all their lung functions, FEV-1, FVC, PEF,FEV-1/FVC ratios, SaO2, Nitric oxide, coughing rates, nasalinflammation.

Results: Treatment with the 20 mM Sodium Pyruvate Saline Nasal Spraywith Calcium Chloride, Magnesium Chloride, and Potassium Phosphate.

The patients that had both diseases, Pulmonary Fibrosis and COPD, showeda clinically significant improvement in lung functions as determined bychanges in FEV-1, FVC, or PEF or FEV-1/FVC ratios on the testing dayscompared to baseline for the 21 day clinical trial while on theirmedications. The 20 mM sodium pyruvate saline nasal spray with thesurfactant enhancers ingredients did enhance the effect of anymedication used to treat patients with both pulmonary fibrosis and COPD.This group of patients showed very little responses to medicationsbecause of the double nature of the two diseases they have.

Results: Treatment with the 20 mM Sodium Pyruvate Nasal Spray withCalcium Chloride, Magnesium Chloride, and Potassium Phosphate(Surfactant Enhancer Ingredients), in Patients with Both PulmonaryFibrosis and COPD and Patients with Idiopathic Pulmonary Fibrosiswithout COPD.

When patients that had both Pulmonary Fibrosis and COPD wereadministered the 20 mM sodium pyruvate formula with the correctconcentrations of calcium chloride, magnesium chloride, and potassiumphosphate, (surfactant enhancer), a significant improvement wasdemonstrated in FEV-1, FVC, or PEF and FEV-1/FVC ratio, which increasedfrom 67% to 87% while on or off their medications. This same result wasalso observed in all patients with Idiopathic Pulmonary Fibrosis withoutCOPD as determined by improvements in FEV-1, FVC, or PEF or FEV-1/FVCand FEV-1/FVC ratios from 51% to 87%, while on or off their medications.This formula produced clinically significant results that was superiorto other formulas tested and showed that current therapies have noeffect on patients with pulmonary fibrosis. The data for both groups,from this study also showed that coughing was significantly (p=0.005)reduced in all patients by day 14; a significant (p=0.011) improvementin nasal irritation/erythema with most patients being free of irritationby day 12 (p=0.000) and a significant (p=0.010) increase in the groupaverage expelled-NO by day 6.

The Sodium Pyruvate with the Surfactant Enhancer Increased Nitric Oxidein the Nasal Cavity that Inhibits Coughing, Post Nasal Drip and MouthBreathing.

The upper and lower airways form one contiguous and functionally relatedorgan that is critical to normal lung functions. The nasal cavityproduces 900-1,100 parts per billion of nitric oxide, which is used tokill invading bacteria, fungi, and viruses compared to the lungs whichproduce 4-48 parts per billion nitric oxide. Nasal nitric oxide alsoproduces clinically useful bronchodilation and has been shown to reducepulmonary fibrosis. Blockage of nasal nitric oxide by inflammationreduces the amount of nitric oxide reaching the lungs, which reducescritical lung functions, leading to increased lung and nasal infections,a reduced SaO₂ level, reduced FEV-1 levels also leading to mouthbreathing and coughing. Nasal steroids and other OTC nasal treatmentsshut down the synthesis of nasal nitric oxide, which then leads todecreased lung functions and a 34% increase in infections.

Example XXV: Tissue Culture Studies that Demonstrate that Lung Fibrosiscan be Reversed Using Sodium Pyruvate with the Surfactant EnhancerIngredients to Target Myofibroblasts

In experiments using lung tissues from patients with pulmonary fibrosisand/or IPF, it was demonstrated that the reversal of lung fibrosis andthe underlying cellular mechanisms were affected by the use of the 20 mMsodium pyruvate saline formula with the addition of calcium chloride,magnesium chloride and potassium phosphate (surfactant enhanceringredients).

Cellular activity was lower in myofibroblast cells within fibroticregions of human lung tissue from pulmonary fibrosis and/or IPFpatients. Myofibroblasts deposit extracellular collagen fiber as part ofthe fibrosis process. Structural changes to the airway are believed tocontribute to an irreversible decrement in lung function in theseindividuals. Subepithelial deposition of collagen (types I, III, and V)and other extracellular proteins, fibroblast proliferation, mucushypersecretion, and smooth muscle thickening are all evident in airwayremodeling in pulmonary Fibrosis. Other cellular components may not onlystimulate differentiation of fibroblasts to myofibroblasts, but alsoinhibit apoptosis of the myofibroblasts in the lung parenchyma causingextended survival of this population and excessive collagen deposition,which causes fibrosis.

Activation of myofibroblasts apoptosis from lungs of humans withpulmonary Fibrosis, using the 20 mM sodium pyruvate saline nasal spraywith the addition of calcium chloride, magnesium chloride and potassiumphosphate (surfactant enhancer ingredients) led to lower fibroticactivity also enhanced the production of new mitochondria, theorganelles in cells that produce energy in the myofibroblasts, and itnormalized the cells' sensitivity to apoptosis.

The combination of sodium pyruvate and calcium chloride, potassiumphosphate and magnesium chloride were synergistic in its ability toincrease the incorporation of pyruvate into in myofibroblast cells Itenhanced cellular activity and decreased collagen deposition thatinhibited fibrosis, specifically measured by changes in sub-epithelialmatrix deposition, using histochemical and immunohistochemical staining.In previous studies with rat lungs previously treated with bleomycin,using [2-(14)C] labeled pyruvate; cellular activity and analysis clearlyshowed that the sodium pyruvate, calcium chloride, potassium phosphateand magnesium chloride formula decreased fibrosis by inhibiting cellularenzymes that increase fibrosis.

Gennero Culture Medium Patent Application. 20090181007.

This patent combined dozens of ingredients, including the use of enzyme,growth factors, sugars, nucleotide and vitamins, amino acids and sodiumpyruvate, other nutrients and calcium chloride, magnesium chloride andcalcium phosphate other ingredients to stimulate the growth of cartilageand collagen for knees and joints. We assessed this formula anddiscovered it did stimulate the synthesis of cartilage and collagen,when placed in lung tissue cultures with fibroblasts, thatdifferentiated into myofibroblasts that produced a huge amount tocollagen, which in patients with pulmonary fibrosis would be fatal.Activation of myofibroblasts to increase the synthesis of collagen fromlungs of humans with pulmonary Fibrosis, with the Gennero culture mediumled to more fibrotic activity that did not cause the myofibroblasts tonormalize to undergo apoptosis. Even though this formula containedsodium pyruvate, calcium chloride, magnesium chloride and calciumphosphate it acted in the opposite manner when these ingredients weretested with the other ingredients listed in the culture medium. Onecannot assume you can achieve clinically significant results because aculture medium contained some of the ingredients listed in the membranesurfactant enhancer. The addition of the other ingredients when inhaleddid produce the opposite effect by increasing fibrosis instead ofstopping it. This prior art reference teaches away from the presentinvention methods.

TABLE XI Percentage measurements in patients with pulmonary fibrosis,permanent hypoxemia, IPF and in patients with un meet needs that cannotuse steroids, Diabetics, and Hypertensive patients with FEV-1/FVC ratiosaround 50%. Comparison of various pyruvate nasal spray formula againstthe 20 mM sodium pyruvate formula with calcium chloride, potassiumphosphate and magnesium chloride. Percentages of ingredients in oneliter of water 0.22% sodium pyruvate, 0.9% sodium chloride 0.01% Calciumchloride, 0.01% magnesium chloride and 0.001% potassium phosphate byweight (surfactant enhancer), demonstrated clinical superiority over allother formulas listed. Nasal formula with 0.9% Katz Pat. Nos. sodiumchloride 5,798,388 With 20 mM 5,939,459 Katz formula Nasal formula Nasalformula Nasal formula sodium pyruvate 5,952,384 Katz formula 0.90%Sodium 0.45% sodium with 0.9% with 1.0% and calcium 6,482,856 0.90%sodium chloride With chloride with sodium chloride sodium chloridechloride, magnesium application chloride 0.5 5.0 mM 20 mM sodium with 20mM with 20 mM chloride and 200220006961 mM pyruvate pyruvate pyruvatesodium pyruvate sodium pyruvate potassium phosphate Percentage 10%  11% 20% 26% 28% 72% decrease in coughing Percentage 5% 4%  9% 11% 14% 36%increase in FEV-/ FVC ratios over baseline of 50% Percentage 6% 7% 13%15% 18% 67% decrease in fibrosis Percentage increase 2% 4%  7% 14% 22%77% in apoptosis in myofibroblasts Cell death

Nasal Inhalation Sodium Pyruvate with the Membrane Enhancer DecreaseMouth Breathing to Increase Serotonin Levels Back to Normal Levels.

Nasal inhalation of sodium pyruvate with the membrane enhancers, notonly decreases nasal inflammatory agents, it reduces mouth breathing toincrease the synthesis of nitric oxide to normal levels which maintainsnormal levels of serotonin. With the reduction of nasal nitric oxide dueto congestion, inflammation and mouth breathing, normal levels ofserotonin drop. Serotonin is one of the most widely recognized of allneurotransmitters. It is intricately involved in numerous core physicalprocesses such as the regulation of sleep, appetite and aggression.Serotonin is also a key player in mood, anxiety, fear, and general senseof well-being. Imbalances in serotonin, particularly relative tonorepinephrine and dopamine, are common causes of certain types ofdepression. Antidepressants that block serotonin's re-uptake back intoserotonin neurons are among the most common of all classes ofmedications prescribed. Serotonin deficiency is a common contributor tomood problems, sleep and is common with patients that have a lung orsinus disease that mouth breath. Nitric oxide is needed to maintainnormal levels of serotonin to maintain normal health.

Serotonin Urine Tests.

Eleven patients with various lung and sinus diseases including COPD,allergic rhinitis, chronic rhinosinusitis and pulmonary fibrosis wereinstructed to use the 20 mM sodium pyruvate nasal spray (0.22% Sodiumpyruvate, 0.9% sodium chloride, 0.01% Calcium chloride, 0.01% magnesiumchloride and 0.001% potassium phosphate by weight per liter of water)for two weeks. Urine samples were collected from these patients prior tousing the nasal spray and two weeks later and compared. All patients hadbelow normal levels of serotonin when compared to normal individuals.The 5-hydroxyindoleacetic acid (5-HIAA) urine test is used to helpdiagnose and monitor serotonin levels. It may be ordered by itself oralong with a blood serotonin and/or chromogranin A level. 5-HIAA is theprimary metabolite of serotonin that is excreted in the urine. Theformula tested and listed above increased serotonin levels over 62%above base line measurements to bring the serotonin back to normallevels. Mouth breathing disappeared as did coughing, all lung functionsincreased and anxiety, fear disappeared and general sense of well-beingoccurred.

Nitric Oxide is Elicited and Inhibits Viral Replication in Pigs Infectedwith Porcine Respiratory Coronavirus

We examined NO levels by Greiss assay in bronchoalveolar lavage (BAL) ofpigs infected with either porcine respiratory coronavirus (PRCV). Theantiviral effects of NO on this virus was tested in an in vitro systemusing a NO donor, S-nitroso-N-acetyl penicillamine (SNAP). We detected alarge increase in NO levels in BAL fluids of PRCV-infected pigs.Pulmonary epithelial cell necrosis induced by PRCV coincided withincreased NO. Moreover, NO levels in cell culture medium ofPRRSV-infected alveolar macrophages (AMs) did not differ from that ofmock-infected AMs. Antiviral assays showed that NO significantlyinhibited PRCV replication in swine testicular (ST) cells. NO plays arole in innate immunity to respiratory CoV infections by inhibitingviral replication.

Although particular embodiments of the invention have been described indetail herein with reference to the accompanying drawings, it is to beunderstood that the invention is not limited to those particularembodiments, and that various changes and modifications may be effectedtherein by one skilled in the art without departing from the scope orspirit of the invention as defined in the appended claims.

CONCLUSIONS

Comparison of the various sodium pyruvate formulations including any 20mM sodium pyruvate saline nasal spray to the 20 mM sodium pyruvate nasalspray with calcium chloride, magnesium chloride, and potassium phosphate(surfactant enhancer ingredients) in patients with Pulmonary Fibrosiswith and without COPD, diabetics and patients with hypertension,demonstrated superiority in increasing lung functions, and the FEV-1/FVCratios from 51% to 87% and achieving relief in the patients over theother sodium pyruvate saline nasal spray by itself, without thesurfactant enhancer ingredients, especially in patients with bothPulmonary Fibrosis and COPD. All formulation decreased inflammation butnot all formulas decreased fibrosis or collagen deposition significantlyor increased apoptosis in myofibroblasts. The use of the 20 mM sodiumpyruvate nasal spray with calcium chloride, magnesium chloride, andpotassium phosphate (surfactant enhancer ingredients) resulted in:

-   -   1. A significant unexpected improvement in lung function        (breathing) in all patients with pulmonary Fibrosis with or        without COPD) compared to baseline, as determined by changes in        FVC, FEV₁, PEF, and FEV-1/FVC ratios while on their medications.    -   2. Coughing and mouth breathing was significantly reduced with        the 20 mM sodium pyruvate nasal spray with the surfactant        enhancer ingredients, and continued to decrease over the course        of the daily treatment.    -   3. A significant increase in the group average expelled-NO        (nitric oxide), with the 20 mM sodium pyruvate nasal spray with        the surfactant enhancer ingredients in all patients showing an        increase during the study.    -   4. Improvement in endurance and exercise was reported with the        20 mM sodium pyruvate nasal spray with the surfactant enhancer        ingredients in all patients    -   5. A significant (p=0.011) improvement in nasal        irritation/erythema with the 20 mM sodium pyruvate nasal spray        with the surfactant enhancer ingredients with most patients        being free of irritation by day 12 (p=0.000)    -   6. Serotonin came back to normal levels. Mouth breathing        disappeared as did coughing, all lung functions increased,        anxiety and fear disappeared and general sense of well-being        occurred with the 20 mM sodium pyruvate nasal spray with the        surfactant enhancer ingredients.    -   7. Increasing cellular protection and deactivation of        myofibroblasts collagen deposition from lungs of humans with        pulmonary Fibrosis and IPF to repair and reverse lung fibrosis,        with the 20 mM sodium pyruvate nasal spray with the surfactant        enhancer ingredients    -   8. Increase in apoptosis in myofibroblasts with the sodium        pyruvate formula that contained the surfactant enhancer        ingredients.    -   9. Inhibits replication of the coronavirus with the 20 mM sodium        pyruvate nasal spray with the surfactant enhancer ingredients.

What is claimed is:
 1. A method of stimulating the synthesis of humanand animal patient lung and sinus surfactants for treatment of lungdamage needed to increase lung functions, increase oxygen levels,increase the synthesis of nasal nitric oxide and for inhibition of lungfibrosis while reducing, coughing, lung tightness, mouth breathing, andreducing congestion, for treating patients with a pulmonary conditionincluding asthma, chronic obstructive pulmonary disease, cysticfibrosis, interstitial lung disease, pulmonary fibrosis, allergicrhinitis, sinusitis, sleep apnea and lung cancer, which comprises:contacting mammalian cells with a therapeutically effective amount of acomposition, said composition including the following constituents: a)sodium pyruvate; b) a phosphate; c) a salt of calcium; and, d) a salt ofmagnesium; wherein said composition contains the following amounts ofsaid constituents: sodium pyruvate ranges from about 0.0001 mg to about1 gram; and ranges from 0.0001 mg to about 1 gram for each of thefollowing constituents: phosphate, salt of calcium and salt ofmagnesium.
 2. The method of claim 1 wherein said composition is a salinesolution.
 3. The method of claim 1, wherein the phosphate is selectedfrom the group consisting of calcium phosphate, a potassium phosphate,magnesium phosphate, and zinc phosphate, and combinations thereof. 4.The method of claim 3, wherein said phosphate is a calcium phosphateselected from the group consisting of calcium phosphate, di-calciumphosphate and combinations thereof.
 5. The method of claim 3, whereinsaid phosphate is a potassium phosphate selected from the groupconsisting of potassium phosphate, di-potassium phosphate, tri-potassiumphosphate, and combinations thereof.
 6. The method of claim 1, whereinsaid salt of calcium is selected from the group consisting of calciumchloride, calcium carbonate, calcium acetate, calcium citrate, calciumlactate, calcium sulfate, and combinations thereof.
 7. The method ofclaim 1, wherein said salt of magnesium is selected from the groupconsisting of magnesium chloride, magnesium phosphate, magnesiumsulfate, magnesium bicarbonate, and combinations thereof.
 8. The methodof claim 1, wherein the phosphate is selected from the group consistingof calcium phosphate, a potassium phosphate, magnesium phosphate, andzinc phosphate, and combinations thereof, and wherein said salt ofmagnesium is selected from the group consisting of magnesium chloride,magnesium phosphate, magnesium sulfate, magnesium bicarbonate, andcombinations thereof.
 9. The method of claim 1, wherein said salt ofmagnesium is selected from the group consisting of magnesium chloride,magnesium phosphate, magnesium sulfate, magnesium bicarbonate, andcombinations thereof, and wherein said salt of calcium is selected fromthe group consisting of calcium chloride, calcium carbonate, calciumacetate, calcium citrate, calcium lactate, calcium sulfate, andcombinations thereof.
 10. The method of claim 1, wherein the phosphateis selected from the group consisting of calcium phosphate, a potassiumphosphate, magnesium phosphate, and zinc phosphate, and combinationsthereof, and wherein said salt of calcium is selected from the groupconsisting of calcium chloride, calcium carbonate, calcium acetate,calcium citrate, calcium lactate, calcium sulfate, and combinationsthereof.
 11. The method of claim 1, wherein the phosphate is selectedfrom the group consisting of calcium phosphate, a potassium phosphate,magnesium phosphate, and zinc phosphate, and combinations thereof, andwherein said salt of magnesium is selected from the group consisting ofmagnesium chloride, magnesium phosphate, magnesium sulfate, magnesiumbicarbonate, and combinations thereof, and wherein said salt of calciumis selected from the group consisting of calcium chloride, calciumcarbonate, calcium acetate, calcium citrate, calcium lactate, calciumsulfate, and combinations thereof.
 12. The method of claim 1, whereinsaid composition is a saline solution containing sodium pyruvate,calcium chloride, potassium phosphate and magnesium chloride ions insolution.
 13. The method of claim 1, wherein said composition containsthe following amounts of said constituents: sodium pyruvate ranges fromabout 0.01 mg to about 1 gram; and ranges from 0.0001 mg to about 1 gramfor each of the following constituents: phosphate, salt of calcium andsalt of magnesium.
 14. The method of claim 1, wherein said compositioncontains the following amounts of said constituents: sodium pyruvateranges from about 0.01 mg to about 1 gram; and ranges from 0.0001 mg toabout 1 gram for each of the following constituents: phosphate, salt ofcalcium and salt of magnesium.
 15. The method of claim 11, wherein saidcomposition contains the following amounts of said constituents: sodiumpyruvate ranges from about 0.01 mg to about 1 gram; and ranges from0.0001 mg to about 1 gram for each of the following constituents:phosphate, salt of calcium and salt of magnesium.
 16. The method ofclaim 12, wherein said composition contains the following amounts ofsaid constituents: sodium pyruvate ranges from about 0.01 mg to about 1gram; and ranges from 0.0001 mg to about 1 gram for each of thefollowing constituents: phosphate, salt of calcium and salt ofmagnesium.
 17. The method of claim 1, wherein a therapeutic agent isadministered prior to contacting said mammalian cells with saidcomposition.
 18. The method of claim 1, wherein a therapeutic agent isadministered simultaneously with contacting said mammalian cells withsaid composition.
 19. The method of claim 1, wherein a therapeutic agentis administered after contacting said mammalian cells with saidcomposition.
 20. The method of claim 1, wherein said method includescancer treatment and an oral diet is administered before and after saidcancer treatment and said oral diet includes the composition set forthin the method of claim 1.